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Published Date: 2012-01-26 20:50:34
Subject: PRO/AH/EDR> E. coli EHEC - Europe: (France, Germany, Denmark) O104
Archive Number: 20120126.1022870

E. COLI EHEC - EUROPE: (FRANCE, GERMANY, DENMARK), O104
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Date: Thu 26 Jan 2012
Source: Eurosurveillance, Volume 17, Issue 4 [edited]
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20065

On 30 Sep 2011, the University Hospital of Caen in western France informed the local health authorities of 2 cases of post-diarrhoeal hemolytic uremic syndrome (HUS) in adults returning from an organised bus tour in Turkey that had taken place between 4 and 17 Sep 2011. Both cases were women in their 60s. They had not known each other prior to their journey to Turkey. Diarrhea onset was 15 Sep 2011 for both cases. They were hospitalized following their return from Turkey, and HUS was diagnosed on 20 and 26 Sep 2011. Initial information obtained from the concerned travel agency indicated the occurrence of additional cases of diarrhea among other members of this travel group during the trip to Turkey.

Epidemiological investigation
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A case was defined as a person with diarrhea, bloody diarrhea or HUS, with a date of symptom onset between 4 Sep and 2 Oct 2011 who was a member of the group having traveled to Turkey between 4 and 17 Sep 2011. A case of HUS was defined as acute renal failure and either microangiopathic hemolytic anaemia and/or thrombocytopenia.

The tour operator was contacted to identify any additional cases among individuals of groups who subsequently travelled on the same bus tour.

All 22 travelers of the group were interviewed using a standardised semi-structured questionnaire exploring symptoms, food consumption including sprouts, activities undertaken during the trip to Turkey, and contact with animals or other cases of diarrhea in the 7 days before symptom onset.

Case description
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As of 4 Oct 2011, 6 additional cases were identified, bringing the total number of cases to 8. Among the 8 cases, 6 were women, and 2 were men with a median age of 64 years (range: 51-71 years). Five cases presented with diarrhea, one case initially with diarrhea and a 2nd episode of bloody diarrhea 4 days later, and 2 cases with bloody diarrhea evolving into HUS. Cases had symptom onset between 6 and 15 Sep 2011 with an initial group of 5 cases occurring on 6 and 7 Sep 2011 and 3 cases occurring later during the trip (Figure 1, [For all figures, see original URL. - Mod.LL]). One case consulted a hospital emergency room for bloody diarrhea during the trip and was not admitted. Both HUS cases were hospitalized following their return to France. One HUS case was discharged after 5 days of hospitalization, while the 2nd case, who had a transient ischemic attack, was discharged after 9 days of hospitalisation.

The group's 2-week bus itinerary in Turkey took them from Istanbul to Ankara, Cappadocia, Aksaray, Konya, Pamukkale, Aphrodesia, Kudsadai, Priene, Miletus, Didymus, Izimir, Seljuk, Pergamum and Bursa. Due to the relatively long stay in Turkey and the fact that the group stayed in 9 different hotels and repeatedly ate similar foods in numerous restaurants, often with buffet style meals, we were unable to identify a specific food that might have been associated with illness. While group members could usually remember having eaten a certain food item, they could not remember on what date, how often or during which specific meals they had consumed this item. No member of the group reported having eaten sprouts during the trip to Turkey or before departure to Turkey.

Following the initial interview, a 2nd questionnaire focusing specifically on food items eaten at the airport before boarding the plane, during the flight from Paris to Istanbul on 4 Sep 2011 and during the 1st 2 days of the tour was undertaken. The objectives were to exclude the hypothesis of contamination before arrival in Turkey and to identify a food consumed during the 1st 48 hours after arrival in Turkey that could have explained the 5 initial cases. Information on the menus served during the flight from Paris to Istanbul was obtained from the airline's catering company. Group members reported no common meal or food shared before boarding the plane in Paris, and none brought food to the airport to share among the group. Two menus were available during the flight with a choice of poultry or smoked fish as a main course. Neither menu was common to all cases. The group members had difficulty remembering specific foods items served during the 48 hours after arrival in Turkey. These data were not sufficiently robust for further analysis.

Microbiological and serological investigation
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Shiga toxin-producing _E. coli_ (STEC) O104:H4 possessing the gene stx2 but not the genes coding for intimin (eae) and hemolysin (hlyA) was isolated from one of the HUS patients. The strain was also negative for the gene coding EAST1 toxin (astA) and positive for the aggA gene which encodes the aggregative adherence fimbriae type I (AAF/I). Analyses on the stool of the 2nd HUS patient were negative for STEC O104:H4. The STEC O104:H4 isolate had the following antibiotic resistance profile: ampicillin-resistant (R), streptomycin R, sulphonamide R, trimethoprim R, cotrimoxazole R, tetracycline R, nalidixic acid R, cefotaxime-sensitive (S), ceftazidime S, imipenem S, kanamycin S, gentamicin S, chloramphenicol S, and ciprofloxacin S. Except the absence of an extended-spectrum beta-lactamase, the resistance profile of this isolate was similar to the profile of the strain involved in the recent STEC O104:H4 outbreaks in Germany and Bordeaux in France linked to the consumption of sprouts in May-June 2011 (1,2).

The strain isolated from the HUS case returning from Turkey was compared by pulsed-field gel electrophoresis (PFGE) using XbaI and NotI (3) to STEC O104:H4 stx2 strains isolated from 2 imported cases in France linked to the German 2011 outbreak, 10 patients in the Bordeaux outbreak in 2011, and 2 sporadic cases isolated in France in 2004 and 2009 (Figures 2 and 3). Previous molecular analyses had shown the genetic relatedness of the Bordeaux and German O104:H4 strains (1). The XbaI- and NotI-PFGE profiles of the strain isolated from the HUS case returning from Turkey were close but not identical (differences in 2 bands for XbaI and in 3 bands for NotI) to those of the German and Bordeaux O104:H4 2011 outbreak strains. PFGE also showed that the strain isolated from the patient returning from Turkey was unrelated to the 2 O104:H4 stx2 aggR agg3A strains isolated previously in France in 2004 and 2009 (4).

In addition, both HUS cases had a positive serology for _E. coli_ O104. Serological testing was performed by a line blot immunoassay using lipopolysaccharides of 7 major serogroups of STEC (O26, O91, O103, O111, O128, O145, O157) and of O104 (extracted from a clinical O104:H4 isolate) (5).

Biological samples were not systematically taken from non-HUS cases as they were no longer symptomatic at the time of the investigation. At the initiative of the treating physician, a stool sample was taken from one case and a serum sample from another, both 28 days after the start of diarrhea. Both analyses were negative.

Control measures
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Colleagues in other European countries were informed of this outbreak on 4 Oct 2011 via the Epidemic Intelligence Information System (EPIS) of the European Centre of Disease Prevention and Control (ECDC) and Early Warning Response System (EWRS) with the request to report any similar cases.

Germany reported the occurrence of 2 adult cases of infection with ESBL-negative STEC O104:H4 stx2 among persons returning from Turkey in July and August 2011. They had developed bloody diarrhea 11 days and 18 after days after returning from Turkey, where both had stayed in Istanbul, and one had additionally spent time at the Black Sea (personal communication, Dirk Werber, January 2012).

Moreover, Danish colleagues reported an STEC O104:H4 stx2 infection in an adult with diarrhea onset on 28 Sep 2011, 2 days before the end of a month's stay in private homes in Ankara (personal communication, Charlotte Kjelso, January 2012).

Contact with the travel agency showed that none of the tourists having subsequently travelled on the same bus tour reported developing diarrhea. As evidence suggested that this outbreak was limited to tourists from this single travel group, no particular control measures were put in place.

Conclusions
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There is no evidence to link this STEC O104:H4 outbreak to the consumption of fenugreek sprouts, as was the case for the German and French outbreaks in May to June 2011 (6-9). None of the 22 travel group members reported the consumption of sprouts before and during their trip to Turkey.

Microbiological or serological evidence of STEC O104:H4 infection was only obtained for the 2 HUS cases. Considering that the median incubation period described for STEC O104:H4 is 8 to 9 days (range: 2 to 18 days) (10) and that these cases developed their symptoms 11 days after their arrival in Turkey, it is probable that they were infected during their stay in Turkey. In addition, these cases did not know each other before their trip to Turkey, they do not live in the same town, and they consumed no common foods before or during their flight to Turkey, which provides further evidence in favor of this hypothesis. No source of contamination could be identified for these cases.

The fact that the 6 initial diarrhea cases did not share a common food before or during the flight to Turkey suggests that they were infected following their arrival in Istanbul. However, their reported incubation period was much shorter than that of the HUS cases. Moreover, none were confirmed as STEC O104:H4 infection. Thus, this cluster may have been due to another pathogen and may have been a distinct event not linked to the HUS cases.

Turkey is among several destinations where European tourists had previously traveled before developing STEC O104 infection between 2004 and 2009 (n=4), along with Afghanistan, Egypt and Tunisia (11). This outbreak supports data suggesting that the STEC serogroup O104 circulates in these areas. Further evidence is provided by the 3 additional cases that were subsequently identified in Germany and Denmark among persons also returning from Turkey within the same approximate time frame. Public health authorities and clinicians should be vigilant for possible STEC O104 infection in individuals returning from these areas who present with post-diarrheal HUS.

References
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1. Mariani-Kurkdjian P, Bingen E, Gault G, Jourdan-Da Silva N, Weill FX: _Escherichia coli_ O104:H4 south-west France, June 2011. Lancet Infect Dis. 2011;11: 732-733.
2. Bielaszewska M, Mellmann A, Zhang W, et al: Characterisation of the _Escherichia coli_ strain associated with an outbreak of haemolytic uraemic syndrome in Germany, 2011: a microbiological study. Lancet Infect Dis. 2011;11: 671-676.
3. Ribot EM, Fair MA, Gautom R, et al: Standardization of pulsed-field gel electrophoresis protocols for the subtyping of _Escherichia coli_ O157:H7, Salmonella, and Shigella for PulseNet. Foodborne Pathog Dis. 2006;3: 59-67.
4. Monecke S, Mariani-Kurkdjian P, Bingen E, et al: Presence of enterohemorrhagic Escherichia coli ST678/O104:H4 in France prior to 2011. Appl Environ Microbiol. 2011;77: 8784-8786.
5. Raoult D, Dasch G: The line blot: an immunoassay for monoclonal and other antibodies. J Immunol Methods. 1989;125: 57-65.
6. Frank C, Werber D, Cramer JP, et al: Epidemic Profile of Shiga-toxin‚Äìproducing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med. 2011;365: 1771-1780.
7. Gault G, Weill FX, Mariani-Kurkdjian P, et al: 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 from: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19905.
8. Buchholz U, Bernard H, Werber D, et al: German outbreak of _Escherichia coli_ O104:H4 associated with sprouts. N Engl J Med. 2011;365: 1763-1770.
9. European Food Safety Authority (EFSA): Tracing seeds, in particular fenugreek (Trigonella foenum-graecum) seeds, in relation to the Shiga toxin-producing _E. coli_ (STEC) O104:H4 2011 Outbreaks in Germany and France. Parma: EFSA; 5 Jul 2011. Available from: http://www.efsa.europa.eu/en/supporting/doc/176e.pdf.
10. Robert Koch Institute (RKI): Final presentation and evaluation of epidemiological findings in the EHEC O104:H4 outbreak, Germany 2011. Berlin: RKI; Sep 2011. Available from: http://www.rki.de/cln_109/nn_217400/EN/Home/EHEC__final__report,templateId=raw,property=publicationFile.pdf/EHEC_final_report.pdf.
11. European Centre for Disease Prevention and Control (ECDC) / European Food Safety Authority (EFSA): Shiga toxin/verotoxin-producing _Escherichia coli_ in humans, food and animals in the EU/EEA, with special reference to the German outbreak strain STEC O104. Stockholm: ECDC; Jun 2011. Available from: http://ecdc.europa.eu/en/publications/Publications/1106_TER_EColi_joint_EFSA.pdf.

[Authors: Jourdan-da Silva N, Watrin M, Weill FX, et al.]

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[It is not surprising that this chimeric enterohemorrhagic/enteroaggregative (EHEAgg) _E. coli_, quite similar but not identical to the strain causing the huge outbreak primarily in Germany in 2011, has continued to be recognized. The vehicle and the mechanism of transmission for this cluster is unclear but has not been formally linked to the previous epidemic. Hopefully, more information can be found from this cluster instead of from a subsequent one.

Since EAgg _E. coli_ seem not to be zoonotic in origin, it is possible that a human asymptomatic food-handler carrier was the source, but this is not evident from the studies to date. - Mod.LL

A HealthMap/ProMED-mail map can be accessed at: http://healthmap.org/r/1hSV.]

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