Eculizumab Offers No Benefit in the Treatment of Hemolytic Uremic Syndrome Caused by , Preliminary Report Finds

When an outbreak of foodborne Shiga-toxin producing Escherichia coli O104:H4 (STEC) hit northern Germany beginning in May 2011, physicians had no established treatment regimen and therefore tried various therapies. By the time the outbreak ended in late July 2011, there were 52 deaths among the 3052 incidences of STEC and 733 confirmed cases of hemolytic uremic syndrome (HUS).

Within a week of the outbreak the German Society of Nephrology developed an online data collection form and registry to track cases of HUS and document the short-term effectiveness of best supportive care, therapeutic plasma exchange (TPE), and, for patients with HUS, TPE with eculizumab (TPE-Ecu). Best supportive care consisted of dialysis, mechanical ventilation, and active fluid management. Eculizumab is a monoclonal antibody that interferes with the terminal components in the activation of the complement cascade.

Jan Kielstein, MD, PhD, associate professor of medicine at the Medical School of Hannover in Germany, presented an analysis of the registry data at the 49th European Renal Association–European Dialysis and Transplant Association Congress in Paris in May. He told Kidney News that the data suggest that the TPE-Ecu combination does not provide any further benefit in the treatment of HUS compared to TPE alone.

Of the 631 entries from 84 centers in the STEC-HUS registry, the investigators confirmed 491 STEC-HUS cases, of which 241 underwent TPE, 193 TPE-Ecu, and 57 best supportive care.

The patients who received best supportive care alone were almost 10 years older on average (55 years) than the TPE and TPE-Ecu groups combined (45 years). Yet patients in the best supportive care group had less severe disease (including hemolysis), less need for dialysis, and a lower frequency of seizures. These patients also had lower serum creatinine at hospital discharge (1.1 mg/dL compared with 1.2 mg/dL and 1.4 mg/dL for the TPE and TPE-Ecu groups, respectively). Very few patients required dialysis at discharge, and there was no significant difference between groups.

However, mortality was significantly higher in the best supportive care group compared to the others: 10.5 percent compared with 3.7 percent and 2.6 percent in the TPE and TPE-Ecu groups, respectively.

Kielstein cautioned that one must examine the raw data from the best supportive care group, especially the mortality data, because the best supportive care group was older than the other groups “and age is an overriding risk factor for death in this patient population.”

Also, of the six patients who died in the best supportive care group, two opted out of further treatment because they had advance directives, and one additional patient died from complications of insertion of the central venous catheter intended for TPE. “This very much illustrates the difficulty looking at those registry online data, and this I think is the main disadvantage from the crisis, that we don’t have prospective controlled data,” Kielstein said.

Further complicating interpretation of the results, disease severity triggered different intensities in treatment, so the less severely ill patients received best supportive care. The most ill patients, especially those with neurological complications, received TPE-Ecu.

While acknowledging the “scarce evidence at best” to support the use of eculizumab, Kielstein explained the rationale for its use in patients with HUS. A few preliminary studies have shown upregulation of the complement system in the active phase of HUS. “But the main triggering event to use eculizumab in these patients was, number one, the safety profile of eculizumab,” he said, “number two, the fact that it was available on compassionate use [so] nobody had to pay for it, and number three, the fact that in the middle of the crisis there was a report in the New England Journal of Medicine (1) showing remarkable recovery of three pediatric patients that were suffering from severe neurological symptoms in the context of STEC-HUS.”

From the registry data, it can’t be determined if antibiotics were useful because data were lacking on the antibiotics used, their time course, and their dosages. Kielstein noted that a recent article in the Journal of the American Medical Association (2) showed that azithromycin can significantly decrease the shedding time of STEC from the gut, possibly prompting a rethinking of a previous recommendation not to use antibiotics in STEC-HUS lest the bacteria release more Shiga toxin as they are destroyed.

As with antibiotics, some hospitals used steroids with TPE and others did not, further complicating the retrospective analysis.

Kielstein suggested that the medical community establish systems now to collect data in a crisis situation and design a fast-track process to approve clinical trial protocols at the start of future crises since the present approval process is unable to react quickly enough.

Notes

[1] The study had no commercial funding. Dr. Kielstein had no disclosures.

References

1.Lapeyraque AL, et al. Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med 2011; 364:2561–2563.

2.Nitschke M, et al. Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin–producing enteroaggregative Escherichia coli O104:H4. JAMA 2012; 307:1046–1052.

July 2012 (Vol. 4, Number 7)