What are the lessons learned so far from the O104:H4 outbreak?
German medical and public health authorities are burdened by the equivalent of more than 10 normal years worth of case loads occurring in a single month, the continuing need for secondary infection prevention, the outbreak source investigation and perhaps other issues as well. Despite this, a major study conducted as the outbreak was peaking was published in the New England Journal of Medicine [1]. This included a prospective study on a subset of patients.
An article [2] and editorial [3] published in Eurosurveillance also presented some key information. The specific content of these reports and their implications for medical and public health response to possible new clusters or outbreaks remains largely unreported, two weeks later. Here are some of the vignettes and possible lessons learned based on these three reports, news articles during the development of the outbreak — largely from Germany — reports from the French outbreak, and other background sources.
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One of the important findings of the prospective study in the NEJM article [1] was that daily laboratory testing for platelet counts, creatinine and lactase dehydrogenase (LDH) were crucial for monitoring the approach of HUS in patients.
It took a median of 5 days, from known (bloody) diarrhea to HUS onset, when this occurred. For the first three days levels were fairly steady, and in fact platelet counts and LDH, if anything, improved. This corresponded with some patients re-porting that they felt they had begun to recover from bloody diarrhea even as HUS was about to rapidly develop.
On day four creatine and lactate dehydrogenase rose modestly, while platelet levels began a somewhat steeper corresponding decline. During day five creatinine levels had tripled over the baseline; lactase dehydrogenase had tripled or quintupled and platelet levels had fallen to about one fifth of baseline (50-60,000 platelets per cubic mm from the chart).
These were the accurate predictors for HUS; indicating kidney damage response (creatinine), tissue damage response (lactase dehydrogenase) and the consequence of blood cell damage (platelet decrease) or hemolysis.
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The Eurosurveillance article [2] presented one of the first highly probable human-to-human transmissions in this outbreak, in this case mother to infant.
Returning from northern Germany to the Netherlands, the mother became ill 8 days later, and the child 15 days later. The mother developed severe HUS 4 days after admission to the hospital for bloody diarrhea. Her child developed “blood abnormalities compatible with HUS,” fever — which appears unusual for these cases — and severe neurological symptoms. Three weeks after admission, as of the reporting date, the child remained on dialysis and had unknown neurological consequences.
This fits with a reported pattern of approximately 8 days for incubation of O104:H4 [1], about twice as long as for O157:H7. The timing of HUS onset also fits with the NEJM description of timing of HUS approximately 5 days after initial admitting symptoms — here bloody diarrhea and abdominal pain for two days for the mother.
Crucially: “The child had spent much time with her mother during her stay at the first hospital, when the mother developed diarrhea. Before admission of the child to (the hospital) the mother had not been advised to take any specific hygienic measures.”
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One of the most important findings reported in the Eurosurveillance editorial [3] was that roughly one half of patients with HUS developed severe neurological symptoms. These included: disorientation, dissociation, stupor, and life-threatening seizures. Neurological symptoms, present in other Shiga toxin-producing E. coli (STEC) outbreaks, are a signature severe partner to HUS and gastroenteritis in outbreaks with this strain of O104:H4 (See also [7]).
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Clinical presentations from this outbreak are quite surprising compared to past experience both with O157:H7 and non-O157 STEC E. coli cases over the last 30 years.
Some of this can be explained, perhaps, by the presumed food carrier being sprouts. Most cases are adults, who may be presumed to be more likely to eat sprouts than those 17 years or younger. More cases are adult women, in particular, than would be expected at random. This also could be explained by dietary choice. The vast majority of deaths are in older and elderly patients. This could be explained by the observation that there still are no effective treatments for HUS in particular, and that the elderly may be less successfully treated by ameliorative or palliative care, or may in fact be more susceptible to harm from some of the treatments.
However, in comparing adults and children, the O104:H4 outbreak is not only different from expectations but backward from previous experience. In the past, HUS has been a disease outcome overwhelmingly of infants and children, but here it is overwhelmingly an adult outcome. Bloody diarrhea is more common in adults while vomiting is more common in children.
The disease course, once started by dietary or human-to-human transmission, is statistically very different for adults and children compared to other STEC.
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Another, much smaller O104:H4 outbreak occurred in the Gironde region of southwest France centered on Begles [4]. This outbreak has 15 cases versus more than 4,000 in the German outbreak. The outbreak strain is consistent with the May-June outbreak strain in Germany.
“Preliminary data indicate that this outbreak shares the same novel epidemiological, clinical and microbiological features identified in the E. coli O104:H4 outbreak in Germany [8], including a predominance of adult women among the cases, an unusually high proportion of HUS cases among identified possible outbreak cases, a longer median incubation period than expected for cases of Shiga toxin-producing E. coli infection, and a genetically related E. coli O104:H4 producing a CTX-M ESBL.”
In this case three kinds of sprouts were produced for a local event. The first food surveys came back with little in common, but further epidemiological questioning showed the initial patients had in fact consumed cold foods decorated with the sprouts at the same event.
Because there is an overlap of a seed supplier with the German sprout producer/farm, fenugreek seeds purchased from Egypt from two different years’ stocks are leading candidates for possible seed-borne transmission through sprouts.
Because of the mult
iple
possibilities of routes of contamination, however, European health authorities are being much more reserved in their comments than earlier. The UK seed company involved in distribution questioned how seeds sold for sprouts to many locations could cause an outbreak in only one location if they were, in fact, the source.
The French case also illustrates a problem raised by U.S. epidemiologists: how to distinguish different reporting criteria when describing the outbreaks. Using the French data, it would look like a 50% transition rate from bloody diarrhea to HUS vs a 20% rate in Germany.
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Medical treatment and follow-up need to be planned before patients see a doctor or are admitted to a hospital until after patients are no longer contagious, if that can be determined.
The mother to child transmission case from the Netherlands shows the terrible individual consequences of the failure to have a system in place for comprehensive care, including family care. In a mass patient event, pre-planning may be critical to limit secondary transmission.
Patients reported in the German press going to doctors or hospitals with preliminary symptoms including diarrhea and stomach cramps, but basically being discharged to return home without treatment or follow-up and told to come back if they developed bloody diarrhea. When this did develop and they returned, they found that while there was segregation of potential STEC patients, the conditions were horrendous, including one bathroom for more 100 patients. Sanitation efforts were quickly overwhelmed. One patient commented that if she wasn’t sick before, she would be now.
German press reports also showed there was great concern and confusion among families of patients about how to treat their family members who were returning home from the hospital. There was apparently a lack of follow up or information provided.
There may need to be special training for both conventional medical staff, social workers or other paraprofessionals to provide accurate care before admission, at admission, and to provide follow-up care and information after returning home in a mass event.
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German press reports showed pro-active actions by public health authorities to prevent child to child transmission in school settings. This included segregating or keeping home children who were ill, shutting down and sanitizing classrooms, and in one case where both food worker employees and children became ill, closing an entire school. It is not clear where children who may have been ex- posed to carriers actually went.
The presumption from O157:H7 experience is that children would be slower to clear STEC from their system than adults, taking a median time of something like 30 days. There also is a reasonable presumption that children may have more difficulty understanding and carrying out basic sanitation, either because of im- maturity or lack of adequate facilities.
O104:H4 may act differently in this regards as well, however. It infects children and adults differently than in O157:H7. If it acts more like some enteroaggrega- tive strains, then adult food handlers may be more of a concern (5), although the complexity of this group makes any generalization difficult (6).
The reports of probable person to person transmission from visitors to Germany to other countries include at least one case in the United States, and possibly two, where the second case was fatal. The impression is that most of these cases, relatively few so far, were adult to adult. Adult transmission should be considered in food handling, indirect hand to mouth transmission through different media such as some cosmetics, or intimate contact, including sex. But there has been little discussion of any of these potential routes.
There have been no reports of multiple transmissions from passengers returning from Germany by air, despite closed, shared facilities.
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Most of the lessons on acute care of O104:H4 won’t be known until the German public health and medical personnel have the time to collate, evaluate and un-derstand their experiences.
There were reports that some physicians and hospitals were trying aggressive early treatment with antibiotics. Normally this is not recommended because of the potential for releasing even more Shiga toxin, but the press reports were that they found normal procedures were not working. These would presumably be antibiotics that O104:H4 does not have resistance markers to. The employment, timing, follow-up, efficacy and consequences for further resistance selection to new classes of antibiotics all have to be a concern.
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In previous STEC outbreaks patients with central nervous system (CNS) dys- function as well as HUS had worse outcomes and mortality. In a 2010 review F. Obata suggested the evidence points to a weakening of both the blood-brain barrier and the blood-cerebrospinal barrier, possibly with the direct involvement of Shiga toxin Stx-2 subtypes involved [8].
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One of the features of clinical treatment in the O104:H4 outbreak has been greater deployment of monoclonal antibodies (MAb’s) targeted at different com- ponents or actions of Stx.
One private company made their MAb drug freely available. This was targeted at disrupting one of two mechanisms of hemolysis, the disruptive triggering of apo- posis, normally a genetically controlled coordinated induction of cell death (9). A second method of triggering hemolysis involving Stx is the disruption of ribo- somal structures in cells preventing protein synthesis and causing cell death [10].
Alison D. O’Brien (10) and her lab at the Uniformed Services University of the Health Sciences in Bethesda MD has conducted some of the key research on monoclonal antibodies to target shiga toxin function and STEC pathogenicity for many years. Some of the commercial products came from earlier research at this lab. A number of animal models have been used by different labs with results that seem consistent with clinical experience (see [11]).
The overall efficacy of MAb’s and passive antibody therapy in the outbreak will be worth learning. There was one point made in the Eurosurveillance editorial [2]:
“Worryingly, especially patients with seizures seemed to respond only weakly to standard antibody-based treatment regimes.”
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There could be a role for vaccination against STEC E. coli, particularly for limited use to prevent li
kely secondary infections alongside other methods [12].
For O157:H7 there are two commercial vaccines developed for cattle. These were tested in herds in both Canada and the United States to see if they would cause a reduction in O157:H7 numbers and shedding, helping protect beef against being a carrier. Apparently they are not being commercially used.
This is a similar situation to West Nile Virus vaccines, where at least three commercial vaccines are available and in use for horses, but none for humans. Vaccine development to prevent STEC infections in people may require a different business or nonprofit model.
Reports on household members of primary cases who remained healthy have shown different levels of antibodies to Stx and to O157:H7 in both IgG and IgM classes. If an IgM was effective at all, oral vaccination might be effective and a more acceptable means of prevention of spread including mass inoculation.
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Author’s note.
I am quite aware of my limitations in preparing this kind of review, but I also note that communication between medical subspecialists and the general public are difficult. Sometimes the general public includes other medical professionals in differing specialties who may be impacted by a new outbreak of O104:H4 yet not have followed the literature from Europe on this issue.
To reflect my lack of expertise, I borrowed the presentation format of the late columnist Herb Caen (San Francisco Chronicle for most of his long career). This was known as “three dot journalism” where he mixed gossip, reporting, social commentary, culture, politics, tragedy and profundity into a city-wide swirl. I suppose one could call this “three dot medical journalism.”
Food Safety News has space for comments, and in this case I would especially invite medical and epidemiological comments to correct errors of content or interpretation or new information.
Daniel B. Cohen
Maccabee Seed Company
Davis. CA
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[1] Epidemic Profile of Shiga-Toxin-Producing Escherichia coli O104:H4 Outbreak in Germany — Preliminary Report
Christina Frank, Ph.D., Dirk Werber, D.V.M., Jakob P. Cramer, M.D., Mona Askar, M.D., Mirko Faber, M.D., Matthias an der Heiden, Ph.D., Helen Bernard, M.D., Angelika Fruth, Ph.D., Rita Prager, Ph.D., Anke Spode, M.D., Maria Wadl, D.V.M., Alexander Zoufaly, M.D., Sabine Jordan, M.D., Klaus Stark, M.D., Ph.D., and Gérard Krause, M.D., Ph.D. for the HUS Investigation Team
June 22, 2011 (10.1056/NEJMoa1106483)
[2] Kuijper EJ, Soonawala D, Vermont C, van Dissel JT. Household transmission of haemolytic uraemic syndrome associated with Escherichia coli O104:H4 in the
Netherlands, May 2011. Euro Surveill. 2011;16(25):pii=19897. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19897
(3) Jansen A, Kielstein JT. The new face of enterohaemorrhagic Escherichia coli infections. Euro Surveill. 2011;16(25):pii=19898. Available online:
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19898
[4] Gault G, Weill FX, Mariani-Kurkdjian , Jourdan-da Silva N, King L, Aldabe B, Charron M, Ong N, Castor C, Macé M, Bingen E, Noël H, Vaillant V, Bone A, Vendrely B, Delmas Y, Combe C, Bercion R, d’Andigné E, Desjardin M, de Valk H, Rolland P. Outbreak of haemolytic uraemic syndrome and bloody diarrhoea due to Escherichia coli O104:H4, south-west France, June 2011. Euro Surveill. 2011;16(26):pii=19905. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19905
[5] Oundo, J. O., Kariuki, S. M., Boga, H. I., Muli, F. W. and Iijima, Y. (2008), High Incidence of Enteroaggregative Escherichia coli Among Food Handlers in Three Areas of Kenya: A Possible Transmission Route of Travelers’ Diarrhea. Journal of Travel Medicine, 15: 31-38. doi: 10.1111/j.1708-8305.2007.00174.x
[6] Q&A: Dr. Robert Tauxe on the Outbreak in Germany, by Daniel B. Cohen, June 22, 2011, Food Safety News.
[7] “Doctors Shaken By Outbreak’s Neurological Devastation; At first, doctors were most concerned about the kidneys of patients with enterohaemorrhagic E. coli, or EHEC. In the past week, howver, it has become apparent that neurologi- cal side effects of the bacterial infection could be even worse”. By SPIEGEL Staff. Spiegel Online 06/09/2011.
[8] Adv Appl Microbiol. 2010;71:1-19. Epub 2010 Feb 20. Influence of Escherichia coli shiga toxin on the mammalian central nervous sys-
tem. Obata F
(9) Induction of apoptosis by Shiga toxins. Vernon L Tesh. Future Microbiol. Author manuscript; available in PMC 2011 January 1.Published in final edited form as:Future Microbiol. 2010 March; 5: 431-453. doi: 10.2217/fmb.10.4.
[10] Mouse Models of Escherichia coli O157:H7 Infection and Shiga Toxin Injec- tion. Krystle L. Mohawk and Alison D. O’Brien. J Biomed Biotechnol. 2011; 2011: 258185. Published online 2011 January 3. doi: 10.1155/2011/258185.
[11] Stx2- but not Stx1-specific human monoclonal antibody protects piglets chal- lenged with enterohemorrhagic Escherichia coli producing Stx1 and Stx2. Kwang-il Jeong, Saul Tzipori, and Abhineet S. Sheoran. Published in final edited form as: J Infect Dis. 2010 April 1; 201(7): 1081-1083. doi:10.1086/651198
[12] Strategies to Reduce Person-to-Person Transmission during Widespread Escherichia coli O157:H7 Outbreak. Edmund Y.W. Seto,* Jeffrey A. Soller,† and John M. Colford Jr. Emerging Infectious Diseases, Vol 13, No. 6, June 2007.