New E coli reports leave major questions hanging

Jun 23, 2011 (CIDRAP News) – A spate of new reports on Germany's huge outbreak of enterohemorrhagic Escherichia coli (EHEC) is emphasizing the idea that the strain is unusually virulent, but the latest findings leave major questions about the outbreak unanswered.

Yesterday the New England Journal of Medicine (NEJM) released a profile of the epidemic that emphasizes the 25% rate of hemolytic uremic syndrome (HUS) and suggests that it is explained by the outbreak strain's "exceptional" virulence.

Today Lancet Infectious Diseases released a microbiologic report on the outbreak pathogen, E coli O104:H4, advancing the argument that it is a hybrid with a special ability to stick to the intestinal walls in clumps, possibly enabling it to pump more Shiga toxin into the bloodstream, leading to the high HUS rate.

However, several veteran foodborne disease investigators told CIDRAP News that it is still premature to conclude that the E coli strain is unusually virulent, because no one knows how many milder E coli infections in the outbreak have gone undetected, leaving the true rate of HUS unknown. They said the more important questions in the outbreak have to do with the original source of contamination and how the epidemic became so large.

On the basis of strong epidemiologic evidence, German officials have cited sprouts from an organic farm in Germany as the likely cause of the outbreak. But how the sprouts became contaminated remains unknown.

The latest reports also include an editorial and two case reports published today in Eurosurveillance. The editorial says German clinicians on a recent conference call reported the unexpected finding that severe neurologic problems developed in about half of their HUS patients in the outbreak. The case reports deal with a patient who needed surgery for colonic ischemia and an instance of secondary EHEC transmission in a family.

A total of 3,802 cases have been reported so far, including 864 HUS cases, for an HUS rate of 22.7%, the World Health Organization said today. A large majority of patients have been adults, most of them women.

An epidemic profile
In the NEJM article, German authors offer a profile of the nationwide epidemic and findings on a series of patients who were prospectively followed at Hamburg University Medical Center.

As of Jun 18, 3,322 outbreak cases had been reported in Germany, including 810 HUS cases (25%), according to the report. Fifty-nine percent of all the patients and 68% of the HUS patients were female. The researchers concluded that the outbreak began on May 8 or 9, with the first patient confirmed with the outbreak strain having gotten sick on May 8.

On the basis of data from 43 patients, the authors estimated the incubation period for the illness at 8 days, as compared with 3 to 4 days for E coli O157:H7, the most common strain of Shiga toxin–producing E coli (STEC).

The authors prospectively followed 135 patients who presented with EHEC-like illness at the medical center. The outbreak strain was detected in 59 (44%) of those patients, and HUS developed in 12 (20%) patients, who did not differ demographically from those who did not have HUS. Development of the syndrome was described as "sudden."

The report lists the 25% HUS rate, the preponderance of adults among HUS cases, and the rare strain as the major differences between the current outbreak and previous ones. It says the high HUS rate occurred despite public advice for people to seek care if they had bloody diarrhea, "which probably led to a more complete ascertainment of gastroenteritis." It also notes that the HUS rate reported from active surveillance of E coli O157:H7 cases in the United States is 6%.

"Taken together, these data suggest that the pathogen in the current outbreak is exceptionally virulent," the report states. But it says that whether "the high proportion of patients with bloody diarrhea reflects the characteristics of the strain or is a consequence of advice to the public to seek medical care" for that condition remains to be determined.

The article says other questions that still need answers include why women are so overrepresented among HUS patients and whether the preponderance of adults mainly "reflects the distribution of exposure or is attributable to the specific properties of this outbreak strain—or both."

More microbiologic details
In the Lancet Infectious Diseases report, researchers from the University of Munster and the Robert Koch Institute offer more microbiologic details about the outbreak strain, based on an analysis of stool samples from 80 patients.

They confirm previous reports that the pathogen is a hybrid that has properties of EHEC and enteroaggregative E coli strains—the ability to produce Shiga toxin and also to stick to intestinal epithelial cells. They also confirmed that the strain has an extended-spectrum beta-lactamase, making it resistant to some antibiotics.

The authors suggest that the pathogen's unusual combination of properties may explain its apparent high virulence: "Augmented adherence of the strain to the intestinal epithelium might facilitate systemic absorption of Shiga toxin and could explain the high progression to haemolytic uraemic syndrome. This outbreak demonstrates that blended virulence profiles in enteric pathogens, introduced into susceptible populations, can have extreme consequences for infected people."

In an accompanying editorial, Hugh Pennington of Aberdeen, Scotland, writes that it is reasonable to believe that the blending of virulence traits explains the high HUS rate in the outbreak. Also, referring to the overrepresentation of adults and women among the HUS patients, he says, "Two factors probably explain this scenario: the patterns of consumption of the vector [food] and an increased likelihood of developing [HUS] because of the high virulence of the clone."

Others say not so fast
However, three Minnesota experts who have investigated many foodborne disease outbreaks said that after the latest reports, there is still not enough evidence to know the real HUS rate in the outbreak or to conclude that the EHEC outbreak strain is unusually virulent.

"In every outbreak we don't ascertain some mild cases, and in this one there's a large potential for underascertainment of a very large number of more mildly affected cases," said Kirk Smith, DVM, MS, PhD, supervisor of the Foodborne, Vectorborne, and Zoonotic Diseases Unit at the Minnesota Department of Health in St. Paul.

"Cases are more likely to seek care and be tested if they have bloody diarrhea," he said. Adding to the uncertainty is a lack of information about the extent to which Shiga toxin tests, which should detect all STEC strains, are used in Germany, he added.

"The best thing they [German investigators] could do to get a truer picture would be to look at the restaurant and cafeteria cohorts they investigated," to find out how many people in those case clusters had nonbloody diarrhea, bloody diarrhea, and HUS, Smith said.

His view was shared by Michael T. Osterholm, PhD, MPH, director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of CIDRAP News, who led foodborne disease investigation when he was Minnesota's state epidemiologist.

"Until we have data on specific cohorts, we won't know the number of HUS cases in relation to the total number of cases," he said. "The media keep repeating that this is a supertoxic bug, but we don't really know that yet."

He said it's likely that many cases early in the outbreak were not tested for Shiga toxin. "There would've been high ascertainment for HUS, and poor ascertainment for the total number of infections."

"The numbers being cited of 25% [for HUS] are just simply not true," he said flatly.

Craig Hedberg, PhD, associate professor of occupational and environmental health at the University of Minnesota School of Public Health, also found fault with aspects of the NEJM report.

"This paper is notable for its lack of exposure information," he commented by e-mail, citing in particular a lack of information on how the authors concluded that the incubation period was 8 days.

"They also puzzle over the age and gender patterns, which are almost certainly a reflection of exposure patterns," Hedberg said, meaning that they are probably explained by the fact that sprouts are eaten mainly by adults, especially women.

"They seem intent on playing up the uniqueness and virulence of the agent, but of course, they are looking at the tip of the iceberg regardless of what they say about advisories to seek medical care if bloody diarrhea ensued," he added. "This messaging would have selected for the bloody diarrhea cases, and underrepresented milder illnesses."

Smith agreed with Hedberg about the demographics of sprouts consumption as an explanation for the age and gender distribution in the outbreak. He said the US spinach-related E coli O157:H7 outbreak of 2006 had similarities to the German outbreak.

In the 2006 outbreak, 71% of patients were female, and in Wisconsin, which had the most cases, about 80% of patients were adults. "It's what you'd expect for spinach, which like sprouts is eaten more commonly by adult females," he said. He noted that the HUS rate in the spinach outbreak was 16%.

Smith said he had not read the Lancet Infectious Diseases report, but he commented, "It's certainly possible that this bug has increased virulence over the usual STECs we see, but I'd just say the evidence as presented is not definitive."

He commented further, "In this outbreak I think the bigger story is just the size of the outbreak and the massive contamination that must've been occurring. I think that should be more the story than the virulence of the bug."

Hedberg concurred. "I would say we just don't really know the relative virulence of this organism, and it ultimately may not matter," he said.

"What does matter is understanding the exposure sources and making sense of where this came from and how that accounted for the outbreak as it occurred. That is the critical weakness of the investigation."

See also:

Jun 22 NEJM report

Jun 23 Lancet Infect Dis microbiology report abstract

Jun 23 Lancet Infect Dis editorial

Jun 23 Eurosurveillance editorial

Jun 23 Eurosurveillance case report on patient who had colonic ischemia requiring surgery

Jun 23 Eurosurveillance report of secondary EHEC transmission in a family

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