The Epidemic Detectives The Hunt for the Source of Germany's E. Coli Outbreak
The eeriest thing of all, according to Rolf Stahl, is the way patients change. "Their awareness becomes blurred, they have problems finding words and they don't quite know where they are," says Stahl. And then there is this surprising aggressiveness. "We are dealing with a completely new clinical picture," he notes.
Stahl, a 62-year-old kidney specialist, has been the head of the Third Medical Clinic and Polyclinic at the University Medical Center Hamburg-Eppendorf (UKE) for almost 18 years. "But none of us doctors has ever experienced anything quite like this," he says. His staff has been working around the clock for the last week or so. "We decide at short notice who can go and get some sleep."
The bacterium that is currently terrifying the country is an enterohemorrhagic strain of the bacterium Escherichia coli (EHEC), a close relative of harmless intestinal bacteria, but one that produces the dangerous Shiga toxin. All it takes is about 100 bacteria -- which isn't much in the world of bacteria, which are normally counted by the millions -- to become infected. After an incubation period of two to 10 days, patients experience watery or bloody diarrhea.
'The Situation Is Deteriorating Dramatically'
But Stahl only sees the most severe cases, those in which EHEC also attacks the blood, kidneys and brain. These patients suffer from a life-threatening complication known as hemolytic-uremic syndrome (HUS). About 10 days after the diarrhea begins, the red blood cells suddenly disintegrate, blood clotting stops working and the kidneys fail. In many cases patients need dialysis to stay alive.
"The situation is deteriorating dramatically for our patients," says Stahl. "And the worst thing is that we don't know what's causing it."
In Germany, about 60 people a year contract hemolytic-uremic syndrome after being infected with EHEC. Last week, there were as many cases in a single day. According to the Robert Koch Institute (RKI), the national German institution responsible for disease control and prevention, there were 276 HUS patients in German hospitals by Friday.
By Tuesday there were 373 confirmed cases of HUS across Germany. As many as 15 people may have died from EHEC in Germany so far in the current outbreak. Cases have also been reported in Sweden, Denmark, Britain, Austria and the Netherlands. Meanwhile Russia has banned imports of cucumbers, tomatoes and fresh salad from Spain and Germany.
Impressive Detective Work
The story of the outbreak began in Stahl's clinic. When the first patient suspected of having contracted HUS was admitted there on a Wednesday evening two weeks ago, none of the doctors had any idea what they were facing. "We weren't even thinking of EHEC at first," says Stahl, "because it normally only affects children." In adults, on the other hand, HUS can also be caused by genetic defects and autoimmune diseases, or as a side effect of cancer treatment.
By the next day, however, there were suddenly seven or eight cases in the ward, and the laboratory reported that they were all infected with EHEC. Hamburg promptly notified the Robert Koch Institute.
The process that began at that point and reached its preliminary climax at the end of last week with the closing of two vegetable production operations in Spain is an example of impressive epidemiological detective work. It involves close cooperation among vigilant doctors, epidemiologists thinking practically and detail-oriented laboratory scientists.
For the disease control experts at the RKI, it was primarily a matter of addressing two tasks simultaneously and as quickly as possible: to find the contaminated food products and to determine the type of bacterium involved.
Extremely Rare
Helge Karch, the director of the RKI's EHEC consulting laboratory at the Münster University Hospital in western Germany, has devoted almost his entire life as a researcher to EHEC bacteria. "But I've never encountered something like this," he says.
The first stool sample arrived in his lab on Monday. The first cases had already appeared in the state of North Rhine-Westphalia by then.
Karch's staff members began their analysis right away. The result was clear by Wednesday evening: It was the extremely rare serotype O104:H4.
Karch spent a sleepless night in front of his computer. The serotype he had identified was so rare that he had only encountered it once in three decades. But had this bacterium ever triggered an epidemic before?
After searching through a database for medical journals, Karch found only one article under the search term "O104:H4": a case study from Korea. In the Korean case, as in most of the German cases, an adult woman had contracted EHEC, which is completely atypical for EHEC.
Plague DNA
Karch kept himself awake with coffee, and to relax he went for walks with his German shepherd. "Can you imagine what I'm going through?" he wrote in an email to Phillip Tarr at Washington University in St. Louis. His response came at 4:27 a.m.: "Epidemics are for younger men." Tarr, the second major EHEC expert next to Karch, had also never heard of an O104:H4 outbreak.
In the email, Karch speculated over why the disease wasn't happening in children, as is normally the case, but only in adults. And why was the infection striking more people that ever before in Germany -- so many, in fact, that dialysis stations in several hospitals were almost full?
Karch and others speculate that the problem could lie in the pathogen itself. Perhaps the genetic material of this rare bacterium has mutated again, so that its toxin or its bond to the intestinal cells it damages has become stronger. Doctors hope that a complete sequencing of the genome, which is now being performed in Münster, will offer some answers.
On Tuesday, the German newspaper Süddeutsche Zeitung reported that Karch had discovered that the O104:H4 bacteria responsible for the current outbreak is a so-called chimera that contains genetic materia from various E. coli bacteria. It also contains DNA sequences from plague bacteria, which makes it particularly pathogenic. There is no risk, however, that it could cause a form of plague, Karch emphasized in remarks to the newspaper.
Reconstructing Patients' Meals
Gérard Krause, head of the infectious epidemiology division at the RKI, had no time to wait for such results. On the morning after the RKI learned of the bizarre cases in Hamburg, four members of Krause's staff made their way to the epicenter of the outbreak, Rolf Stahl's clinic in Hamburg. They brought along the epidemiologist's tool of choice: the questionnaire.
The researchers sat patiently at the bedsides of those patients still in good enough condition to speak with them. Reconstructing all the meals they had eaten in the last few days wasn't easy. "It took hours," says Krause. But the researchers soon noticed something unusual: Hardly any of the patients had eaten raw meat or raw milk, the causes of almost all previous EHEC outbreaks, but almost all of them had eaten uncooked vegetables.
Could that have been the reason why the outbreak primarily affected women, at least at first? Had they become infected while chopping vegetables in the kitchen, or was it simply because women are healthier eaters?
By Monday, a 15-member team from the RKI had been dispatched to conduct a so-called case-control study, using simple tools. "It had to happen quickly," says Krause, "and be prone to as little interference as possible."
Pounding the Pavement
The RKI employees interviewed a total of 25 female patients and compared each woman's responses with those of four healthy women who lived in the same part of Hamburg and were about the same age. "Our people simply approached suitable controls on the street, or they rang random doorbells," says Krause. "It's classic epidemiology, where you simply pound the pavement."
The raw data were then fed into the computers at RKI in Berlin until 2 a.m. that night. By Wednesday morning, Krause was able to present the results: Tomatoes, lettuce or cucumbers were the most likely sources of the infection.
Now the food inspectors knew where to start looking. They had already made an appearance in Eimsbüttel, a Hamburg neighborhood, in the week before last. The first female patient at the UKE in Hamburg was from Eimsbüttel, says Marianne Pfeil-Warnke, the head of the district food safety division. She is sitting in her office on the sixth floor of an administration building, a tall woman with luminous red hair and blue eyes. She keeps her mobile phone on a string around her neck so that she can be reached at all times.
"On Monday, we got the news that the bacteria apparently came from vegetables that grow close to the ground," says Pfeil-Warnke. She sent her inspectors to the supermarkets and vegetable stands where the patients had shopped to gather samples: hearts of romaine lettuce, organic carrots, a Dutch cucumber, tomatoes on the vine, iceberg lettuce, a package of mixed salad greens, a prepared salad with chicken and a tomato-and-mozzarella sandwich.
A kohlrabi was taken from a household where a child had become ill. A man whose wife had contracted EHEC, and who was suffering from stomach pain himself, brought in some tomatoes.
Contaminated Cucumbers
All of the samples -- about 250 by the end of last week -- that Pfeil-Warnke's inspectors and their counterparts in Hamburg's six other districts had collected ended up in Anselm Lehmacher's lab at the Hamburg Institute for Hygiene and Environment. Food biologist Lehmacher is sitting in the library on the fifth floor of the institute wearing a brightly patterned shirt. He is a thoughtful man with a crew cut. The four EHEC-contaminated cucumbers that have since sent the country into an acute cucumber phobia were discovered in his laboratory on Thursday.
From Monday of last week onwards, the food inspectors had been delivering large quantities of fresh vegetables, including samples from the Hamburg central market. "The four positive results were found among those samples," says Lehmacher with a smile and a hint of pride. The positive samples were three cucumbers from Spain and one from somewhere else, possibly the Netherlands, although this was unclear at the end of last week. Two of the cucumbers were organic, says Lehmacher, but he isn't sure about the other ones yet.
Has the most serious risk been averted, now that the blame was placed on the cucumbers? Lehmacher shakes his head. Although the focus is now on the cucumbers and tracing their path to Hamburg, says the scientist, "I'm worried that we'll also find the bacteria in other samples."
On Tuesday of this week, the plot thickened when Hamburg's health minister, Cornelia Prüfer-Storcks, made a surprise announcement that the Spanish cucumbers were probably not the source of the wave of EHEC infections. The bacteria found on two of the four cucumber samples did not match up with the type of EHEC bacteria from the stool samples of patients, she said. "These initial results mean that our hope that we had discovered the source of the (outbreak) has unfortunately not been fulfilled," she added.
Outrage in Spain
Meanwhile, as a result of Lehmacher's discovery, the investigators had now set their sights on Spain. Every year, Germany imports 3 million tons of fruits and vegetables from the Mediterranean country, more than from any other country. Some 80 percent of this produce grows in Andalusia, which was also the source of the three Spanish EHEC-contaminated cucumbers.
But this region, in particular, has long had a bad reputation. Moroccan guest workers work long hours in greenhouses for starvation wages -- and under questionable hygienic conditions. Weren't the Spanish suppliers the obvious culprits in the outbreak?
Not at all, as it turns out, because practices in the region have improved in the meantime. "Spain is now in a good position. The produce is clean," says Manfred Santen, a chemistry expert with the environmental organization Greenpeace. In fact, Spanish farmers have fundamentally changed their working and production conditions.
Not surprisingly, the Spaniards are outraged and feel that they were being made into scapegoats. The two operations where the contaminated cucumbers came from were shut down on Friday evening.
Manure Theory
Wherever it happened, the question of how the pathogen got onto the vegetables was still unresolved by the weekend. The suspicion that liquid manure contaminated the cucumbers seems to make sense, but only at first glance.
The E. coli bacterium is formed in the intestines of ruminants -- cows, sheep and goats -- and reaches the fields in their excrement. Vegetable farmers who have no livestock of their own can buy urine and feces from farm animals from suppliers of so-called liquid manure. As a rule, however, the plants are never in direct contact with the liquid manure, which is spread onto the fields before sowing.
Since the 1980s, the United States has also seen wave after wave of deadly E. coli outbreaks. While searching for the sources of the infection, scientists discovered that the bacteria enter the agricultural cycle through irrigation systems. Canadian scientists found large concentrations of the pathogen in samples taken from wells near US factory farming operations.
But this realization hardly applies to the current European case. In Spain, there is very little livestock in places where fruit and vegetables are cultivated.
Slugs Under Suspicion
Now the scientists are taking a closer look at a group of pests that were previously above suspicion: slugs. Biologists from the University of Aberdeen in Scotland identified the mollusks as potential E. coli carriers -- the bacteria can survive for up to 14 days on the slimy surface of their bodies. Arion vulgaris, the Spanish slug, has long been a problem in Germany, but it's an even bigger and more widespread problem in its native Spain.
Be it liquid manure, water or slugs, cucumbers or lettuce, organic or conventional farms -- whatever the source of the bacteria, the only solution for consumers is to wash their hands. Hand washing is also effective against smear infection, or transmission of the bacteria by way of unwashed hands after using the toilet, but this path of infection is very rare.
Fruit and vegetables are only truly germ-free when cooked. And until now, washing produce with water was seen as an effective way to eliminate the risk, because it was generally understood that E. coli is only found on the surface of produce.
That was until scientists in the department of plant pathology at the Scottish Crop Research Institute in Aberdeen made an alarming discovery: The pathogens apparently felt so comfortable on the tomatoes and lettuce they studied that they migrated from the surface to lower layers of tissue to colonize the fruit.
'Hopefully Everything Will Be All Right'
Perhaps it was these particularly tenacious bacteria that were so disastrous for Caroline E. The 24-year-old student, who is four months' pregnant, has always taken pains to eat healthy food. She usually bought organic vegetables, which she always washed. Now she is on Ward 5B at the UKE, which has been reserved for severe cases of HUS since last Wednesday. A mustachioed guard sits at the entrance to the ward and makes sure that visitors disinfect their hands and put on plastic gloves and protective gowns.
"I've seen people in the ICU who are really in bad shape," says Caroline E., a young woman with smooth, light-brown hair and angular glasses. She says her only symptom is mild diarrhea. In fact, she only went to the doctor after finding out that a work colleague had contracted EHEC. "I just wanted to make sure that I didn't have it," she says. She already had HUS by then.
Doctors aren't sure yet how Caroline's condition will develop, but she seems calm. "I feel better now that I'm in treatment," she says, noting that the doctors assured her that the infection wouldn't harm her unborn child. "If they can only improve my blood counts soon, hopefully everything will be all right," she says.
And then she adds, defiantly: "I can even eat chocolate again."
