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German outbreak leads to drug trial

May 27, 2011 By Marian Turner This article courtesy of Nature News.

Timely discovery of new use for expensive drug put to the test.

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Germany's battle with what now rates as Germany's worst ever outbreak of enterohaemorrhagic Escherichia coli infection hit a new level today with the announcement of a record number of patients suffering life-threatening complications.

Attempting to forestall anticipated deaths, doctors in the north German cities in which the outbreak is centred have set up a spontaneous clinical trial for an experimental antibody drug called eculizumab (Soliris; Alexion), recently listed by Forbes as the world's most expensive.

Adding up

The bacterial infection, known as EHEC, has already claimed at least two lives and infected around 800 people. Almost 300 of those have developed haemolytic uraemic syndrome (HUS), which can cause kidney failure, neurological complications and death.

Infections with EHEC bacteria — which are endemic in cattle but cause diarrhoeal disease in humans — occur intermittently, mostly in children, and are rarely fatal. But most of those affected so far by this outbreak have been young, adult women who were perfectly healthy a week earlier, a demographic that is baffling epidemiologists (see 'Critical hours for E. coli outbreak in Germany').

EHEC cases have now been seen in Denmark, Sweden, the Netherlands and the United Kingdom — mostly in people who have recently been to northern Germany. According to the Berlin-based Robert Koch Institute, the national institute responsible for disease control, the number of HUS cases jumped from 214 on Wednesday to 294 on Friday. Usually only around 60 patients are seen with HUS per year in Germany.

Rolf Stahl, head of the nephrology clinic at the Hamburg-Eppendorf University Hospital, and Reinhard Brunkhorst, president of the German Society of Nephrology, are today rolling out an emergency eculizumab treatment strategy to hospitals across the country.

The drug is currently used to treat a rare disorder of the immune system called paroxysmal nocturnal haemoglobinuria, and a year's treatment costs more than US$400,000. But just this week a study published in the New England Journal of Medicine reported successful use of the drug in treating three patients with HUS1. The drug's manufacturer, Alexion, is now providing eculizumab free of charge in Germany, taking advantage of an unexpectedly large cohort of patients that might help to speed the drug's approval for the treatment of HUS.

Magic bullet

Eculizumab targets a member of the immune system's complement pathway called complement 5. Complement proteins are activated by the Shiga toxin produced by EHEC and are an important component of the immune response to infections. But overactivity of complement proteins, which scientists think occurs in HUS, can lead to tissue damage, particularly in the kidneys. "By blocking complement using eculizumab, we saw a dramatic improvement in the patients' blood-cell counts and kidney function," says Michael Kirschfink at the University of Heidelberg, a co-author on the New England Journal of Medicine paper1.

Brunkhorst and his team at Hanover Medical School are already treating eight patients with eculizumab, and other hospitals are expected to rapidly follow suit. "But we don't want to be overly optimistic," he cautions "we have very little experience with this drug and don't know how effective it will be."

The doctors are also learning on the run. They don't know whether to give the drug during the early stages of renal failure, or only once neurological symptoms set in.

On Wednesday, scientists in Helge Karch's laboratory at the Münster University Hospital confirmed that the current outbreak is caused by a rare strain of E. coli called O104:H4. This strain has never previously been implicated in an outbreak of human EHEC infections. And so while doctors are racing to save patients' lives, scientists are racing to sequence the strain's DNA and understand the biology behind the infection's severity and rapid spread.


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