Frank Et Al 2011 - Epidemic E Coli O104 in Germany

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Epidemic Profile of Shiga-ToxinProducing 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 Grard Krause, M.D., Ph.D., for the HUS Investigation Team*
A BS T R AC T
Background
In this report, we provide a preliminary description of an ongoing large outbreak of gastroenteritis and the hemolyticuremic syndrome caused by Shiga-toxinproducing Escherichia coli in Germany in May and June 2011.
Methods
We analyzed data from reports in Germany of Shiga-toxinproducing E. coli gastroenteritis and the hemolyticuremic syndrome and clinical information on patients presenting to Hamburg University Medical Center. An outbreak case was defined as a reported case of the hemolyticuremic syndrome or of gastroenteritis in a patient infected by Shiga-toxinproducing E. coli, serogroup O104 or serogroup unknown, with an onset of disease on or after May 1, 2011, in Germany.
Results
From the Departments of Infectious Disease Epidemiology (C.F., D.W., M.F., M.H., H.B., M.W., K.S., G.K.) and Infectious Diseases (A.F., R.P.) and the Postgraduate Training for Applied Epidemiology Program (M.A.), Robert Koch Institute, Berlin; and the Department of Internal Medicine, University Medical Center Hamburg-Eppendorf (J.P.C., A.Z., S.J.), and the Health Department of the Hamburg Northern District (A.S.) both in Hamburg, Germany. Address reprint requests to Dr. Werber at werberd@rki.de. Drs. Frank and Werber contributed equally to this article. *The members of the HemolyticUremic Syndrome (HUS) Investigation Team are listed in the Supplementary Appendix. This article (10.1056/NEJMoa1106483) was published on June 22, 2011, and updated on June 24, 2011, at NEJM.org. N Engl J Med 2011.
Copyright 2011 Massachusetts Medical Society.
As of June 18, 2011, a total of 3222 outbreak cases (including 39 deaths) have been reported in Germany, 810 of which (25%) involved the hemolyticuremic syndrome. The outbreak is centered in northern Germany and peaked around May 21 to 23. Most of the patients in whom the hemolyticuremic syndrome has developed are adults (89%; median age, 43 years), and women are overrepresented (68%). The estimated median incubation period is 8 days, with a median of 5 days from the onset of diarrhea to the development of the hemolyticuremic syndrome. Among 59 patients infected with the outbreak strain who were prospectively followed at Hamburg University Medical Center, the hemolyticuremic syndrome developed in 12 (20%), with no significant difference between patients in whom the syndrome developed and those in whom it did not with respect to sex or reported initial symptoms and signs. The outbreak strain was typed as an enteroaggregative Shiga-toxinproducing E. coli O104:H4, producing extended-spectrum beta-lactamase.
Conclusions
In this large outbreak of the hemolyticuremic syndrome, caused by an unusual strain of Shiga-toxinproducing E. coli, cases have occurred predominantly in adults, with a preponderance of cases occurring in women. The hemolyticuremic syndrome has developed in a quarter of the symptomatic outbreak cases that have been ascertained thus far.
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10.1056/nejmoa1106483 nejm.org
The New England Journal of Medicine Downloaded from nejm.org on June 30, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.
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(Stx) in E. coli isolates or of its encoding gene (stx) in stool enrichment culture or isolates must, by law, be reported by diagnosing laboratories to local health departments. This reporting process allows the identification of Shiga-toxinproducing E. coli infection independently of serogroup (serotyping information is requested but not required). The German case definition of Shigatoxinproducing E. coli gastroenteritis (without the hemolyticuremic syndrome) requires, besides laboratory confirmation, the presence of at least one of the following symptoms: diarrhea (three or more loose stools in a 24-hour period), abdominal cramps, or vomiting. In addition, physicians are required to report clinical symptoms compatible with diarrhea-associated hemolyticuremic syndrome in a patient. The German case definition of the hemolytic uremic syndrome comprises thrombocytopenia (platelet count of <150,000 per cubic millimeter), hemolytic anemia, and acute renal dysfunction. The third criterion is met if at least one of the following findings is present: an increase in the serum creatinine level (unspecified), oliguria, anuria, proteinuria, or hematuria. Reported cases of the hemolyticuremic syndrome or Shiga-toxinproducing E. coli infection are investigated and recorded by the local health department, and the reports are forwarded electronically, without identifying information, through the state to the federal level. To minimize the delay that might result from the local investigation of the details of a case, the Robert Koch Institute, on May 23, asked all health departments to immediately forward all case reports of suspected or confirmed hemolyticuremic syndrome, relying on the diagnoses of the notifying clinicians. Case details such as clinical and microbiologic information are to be added to the record by local health departments in the future. Disease onset was defined as the onset of diarrhea, regardless of whether the hemolytic uremic syndrome developed at a later date. An outbreak case was defined as a reported case of the hemolyticuremic syndrome or a reported case of gastroenteritis in a patient infected by ShigaMe thods toxinproducing E. coli, of serogroup O104 or unGerman Surveillance System known serogroup, with a disease onset on or afAccording to the German Protection against In- ter May 1, 2011, in Germany. We describe here fection Act of 2001, the detection of a Shiga toxin data from the national reporting database on inn May 19, 2011, the Robert Koch Institute, Germanys national-level public health authority, was informed about a cluster of three cases of the hemolyticuremic syndrome in children admitted on the same day to the university hospital in the city of Hamburg. On May 20, a team from the Robert Koch Institute arrived in Hamburg to assist with the public health investigation. It quickly became clear that the case numbers were continuing to rise, that there were also cases in adults, and that other areas of Germany, especially northern Germany, were also affected. An investigation of the outbreak involving all levels of public-health and food-safety authorities was initiated to identify the causative agent and the vehicle of infection in order to prevent further cases of disease. The hemolyticuremic syndrome, which was first described in children in the 1950s,1 is characterized by the triad of acute renal failure, hemolytic anemia, and thrombocytopenia. Diarrheaassociated hemolyticuremic syndrome occurs primarily in children, and a precipitating infection with Shiga-toxinproducing Escherichia coli, mainly of serotype O157:H7, is the primary cause.2 The usual reservoir for these bacteria is ruminants, particularly cattle. Human infection with Shiga-toxinproducing E. coli occurs through the inadvertent ingestion of fecal matter for example, through contaminated food or water or through contact with animals or their farm environment or, secondarily, through contact with infected humans. In contrast, the hemolyticuremic syndrome with prodromal diarrhea, indicating an infectious cause, is a rare event in adults. For example, from 1989 through 2006, only 21 of the 322 adults (7%) listed in the Oklahoma registry as having thrombotic thrombocytopenic purpura or the hemolyticuremic syndrome presented with bloody diarrhea.3 This report provides descriptive epidemiologic, clinical, and microbiologic information on this unusual outbreak. It will be updated after the outbreak has finally ceased, in order to provide a complete picture.
Shiga-ToxinProducing E. coli Outbreak in Germany
fectious diseases as of June 18, 2011, at 6 p.m. Central European Summer Time. The preliminary descriptive analysis focuses primarily on reported cases of the hemolyticuremic syndrome in Germany as an indication of the entire outbreak. To show the outbreak area, a map of the incidence of the disease according to county is provided (Fig. 2). Since many cases even within Germany are apparently travel-related, a map showing the incidence according to the patients residence would be misleading. Therefore, for each presumed county of infection, we counted in the numerator both cases among residents of the county who did not have a history of travel and those among case patients who resided elsewhere and had a history of travel to that county; the denominator was the residential population of the county.
Clinical Information
We analyzed clinical data from two groups of patients at the Hamburg University Medical Center (HUMC): patients at their first presentation to the HUMC between May 19 and June 1 who were positive for stx (data extracted from electronic medical records) and a cohort of adults who were seen between May 25 and June 6 at a Shiga-toxin producing E. coli unit that was set up during the course of this outbreak. The study protocol was approved by the ethics committee of the Hamburg Chamber of Physicians. Patients were enrolled in the study if they presented with bloody diarrhea or if they had any diarrhea after contact with a patient who had Shiga-toxinproducing E. coli infection. All patients provided written informed consent before enrollment. Patients were followed for at least 14 days and were tested for the outbreak strain according to the protocol of the National Consulting Laboratory on HemolyticUremic Syndrome.4 Only data from patients infected by the outbreak strain were included in the analysis. The proportion of patients with the hemolyticuremic syndrome among all patients who were positive for Shiga-toxinproducing E. coli was calculated. Platelet counts and creatinine and lactate dehydrogenase levels were monitored daily.
ther by screening for Stx with the use of one of several commercially available enzyme immunoassays or by detection of stx with the use of polymerase chain reaction (PCR). The National Reference Centre for Salmonella and Other Bacterial Enteric Pathogens confirms, culturally isolates, and characterizes Shiga-toxinproducing E. coli from samples in local or regional laboratories that are positive for Stx or stx. Chromogenic agar mediums for Enterobacteriaceae that are positive for extended-spectrum beta-lactamase (ESBL) are used for isolation of the strain. Biochemical characterization of the strain was performed with the use of various commercially available tests (VITEK, bioMrieux; MicroPlate GN, BIOLOG; and API, bioMrieux). Shiga-toxinproducing E. coli virulence-factor genes (stx1, stx2, eae, and ehx) are detected by established PCR methods.5,6 The presence of virulence-factor genes that are typical of enteroaggregative E. coli, such as aatA, aggR, aap, aggA and aggC, are detected according to established PCR protocols.7 Antimicrobial susceptibility was tested by means of microdilution assays with the use of minimal inhibitory concentrations according to the guidelines of the European Committee on Antimicrobial Susceptibility Testing. Serotyping of Shiga-toxinproducing E. coli followed standard protocols.8 One-enzyme (Xba1) pulsed-field gel electrophoresis was performed on Shiga-toxinproducing E. coli O104:H4 isolates.9 Given the strains properties, a shortened protocol is recommended by the National Consulting Laboratory on Hemolytic Uremic Syndrome4 and is currently used by the National Reference Centre and HUMC for confirmation of the outbreak strain.
Statistical Analysis
For statistical comparisons, the z test was used for proportions, and the MannWhitney U test for age distribution. The incubation period was estimated on the basis of data from selected patients with the hemolyticuremic syndrome or Shiga-toxinproducing E. coli gastroenteritis for whom the date of onset of diarrhea was known and who had stayed in northern Germany for no more than 48 hours. The interval between the date of onset of diarrhea and the date of diagMicrobiologic Analysis nosis of the hemolyticuremic syndrome was Shiga-toxinproducing E. coli infection is diag- calculated with the use of information from the nosed by private microbiologic laboratories ei- clinicians notification form, which was sent
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without identifying information to the Robert Only 1% of the case patients with the hemolytic Koch Institute. uremic syndrome are younger than 5 years of age, which was the median age among case patients with the hemolyticuremic syndrome reported in R e sult s Germany from 2001 through 2010.10 The mediOutbreak Cases an age of all patients reported to have the hemoAs of June 18, 2011, a total of 810 cases of the lyticuremic syndrome in the outbreak is 43 years, hemolyticuremic syndrome, including 27 fatal and the median age is higher for female case cases (3.3%), and 2412 additional cases of Shiga- patients than for male case patients (44 vs. 41 toxinproducing E. coli gastroenteritis (all labora- years, a nonsignificant difference). Among the tory-confirmed), including 12 fatal cases (0.5%), case patients with the hemolyticuremic syndrome were reported in Germany, with onset dates of in the states in the northern Germany outbreak May 1 or later. Thus, the hemolyticuremic syn- area, only those in Hamburg have a median age drome developed in 25.1% of the patients as- (34 years) that is significantly lower than the certained in this outbreak. The outbreak grew median age of the case patients in the four surdramatically starting on May 8; cases of the he- rounding affected states (P<0.001). The median molyticuremic syndrome appeared to peak on age of case patients with the hemolyticuremic May 21 (median date of onset, May 21), and cases syndrome who have died is 74 years (range, 24 to of Shiga-toxinproducing E. coli diarrhea appeared 91, except for one 2-year old boy), and the meto peak on May 22 and 23 (Fig. 1), with a median dian age of patients with Shiga-toxinproducing date of hospitalization for hemolyticuremic syn- E. coli gastroenteritis who have died is 83 years (range, 38 to 89). The incidence of the hemolytic drome of May 24. The three case patients with an onset before uremic syndrome peaks in the age group of 30 to May 8 include two young children (one 4 years of 34 years in the case of women and in the age age and the other 6 years of age), one of whom is group of 25 to 29 years in the case of men (Fig. 3). A total of 68.0% of the case patients with the not a resident of the outbreak area. Both are stxhemolyticuremic syndrome and 58.8% of the positive, but serotypes are not available. Cases of the hemolyticuremic syndrome have case patients with Shiga-toxinproducing E. coli been reported from all 16 states in Germany. The gastroenteritis are female; among the patients in highest incidences are being reported from the the two groups who have died, 77.8% and 58.3%, northern states of Hamburg (10.1 cases per respectively, were female. The proportion of male 100,000 population), followed by SchleswigHol- case patients with the hemolyticuremic syndrome stein (6.7 cases per 100,000), Bremen (2.7 cases per rises among cases with dates of onset in June; 100,000), MecklenburgVorpommern (2.2 cases 47.8% of the patients with an onset of disease in per 100,000), and Lower Saxony (1.7 per 100,000) June are male, as compared with 31.9% of the the northern Germany outbreak area. The patients with a disease onset in May (P = 0.04). outbreak has been almost simultaneous in these Among the case patients with the hemolytic areas. Most of the cases from other states can be uremic syndrome in the five most northern and linked to travel-related exposures in the north- most affected states, 74.3% in Hamburg and ern Germany outbreak area. Figure 2 shows the 65.5% in the surrounding states are female (nonincidence of the disease according to county of significant difference). infection. Aside from two satellite clusters linked On the basis of data from 43 case patients, we to restaurants in eastern North RhineWestpha- estimated that the median incubation period for lia and southern Hesse, the area with high inci- this pathogen in this outbreak was 8 days (interdences (4 to 30 reported cases per 100,000 popu- quartile range, 7 to 9), without an apparent diflation) is centered around the city of Hamburg. ference between cases of Shiga-toxinproducing A total of 89% of the case patients in this out- E. coli gastroenteritis and cases of the hemolytic break in whom the hemolyticuremic syndrome uremic syndrome. Among 79 case patients for has developed are adults (i.e., persons older than whom data on both the date of onset of diarrhea 17 years of age). Among case patients 17 years and the date of onset of the hemolyticuremic of age or younger, the median age is 11.5 years. syndrome are known, the interval from the onset
250 STEC gastroenteritis cases in males STEC gastroenteritis cases in females HUS cases in males 200 HUS cases in females Cases continue to be reported
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No. of Cases
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M a M y1 a M y2 a M y3 a M y4 a M y5 a M y6 a M y7 a M y8 M ay 9 a M y 10 a M y 11 ay M 12 a M y 13 a M y 14 a M y 15 a M y 16 a M y 17 a M y 18 a M y 19 ay M 20 a M y 21 ay M 22 a M y 23 a M y 24 a M y 25 a M y 26 a M y 27 a M y 28 a M y 29 a M y 30 ay Ju 31 n Ju e 1 ne Ju 2 n Ju e 3 n Ju e 4 n Ju e 5 n Ju e 6 n Ju e 7 n Ju e 8 Ju ne 9 n Ju e 10 n Ju e 11 ne Ju 12 ne 13
Date of Disease Onset
Figure 1. Epidemiologic Curve of the Outbreak. Shown are the number of cases of the hemolyticuremic(Frank) Shiga-toxinproducing E. coli (STEC) gastroenteritis, 1st AUTHOR: Werber syndrome (HUS) and ofRETAKE: 2nd according to sex. Only cases with a known date of onset are included here 748 of 810 cases of the hemolyticuremic syndrome and FIGURE: 1 3rd 2166 of 2412 cases of Shiga-toxinproducing E. coli of 4 diarrhea.
ARTIST: ts TYPE: Line Combo 4-C H/T
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children than in of diarrhea to the diagnosis of the hemolyticAUTHOR, PLEASE NOTE: adults (69% [9 of 13 children] Figure has vs. 20% [20 of 98 adults], uremic syndrome was 5 days (interquartile range,been redrawn and type has been reset. P <0.001). Most patients Please check carefully. did not have significantly elevated leukocyte levels 4 to 6). JOB: 364xx ISSUE: xx-xx-11 (most were within the normal range; in some casClinical Information es, counts were approximately 13,000 per cubic Data on 141 patients, obtained at their first pre- millimeter) or C-reactive protein levels (typically sentation to HUMC, were analyzed; 124 of the about 15 to 35 mg per liter [normal level, <5 mg patients (88%) were adults. Among the adults, per liter]). A total of 22 patients (16%) already 66% were women, and the percentage was con- met the criteria for the hemolyticuremic synsistent across age groups; among the children, drome at the time of presentation. Clinical and 50% were girls. No patient had a fever (defined as laboratory values in adults and children, stratia temperature of at least 37.5C) at the first pre- fied according to the presence or absence of the sentation. Bloody diarrhea was reported less often hemolyticuremic syndrome, are summarized in in children than in adults (59% [10 of 17 chil- Table 1. dren] vs. 96% [114 of 119 adults], P<0.001), whereAmong the 135 patients who were followed as abdominal pain was a very common symptom prospectively, the Shiga-toxinproducing E. coli outin both children and adults, occurring in 92% of break strain was detected in 59 (44%), and the the children (12 of 13) and in 89% of the adults hemolyticuremic syndrome developed in 12 of (105 of 118). Vomiting occurred more often in these patients (20%; 95% confidence interval, 11
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Denmark Baltic Sea North Sea
SchleswigHolstein MecklenburgVorpommern Bremen

Netherlands
Hamburg
Poland
Lower Saxony Berlin
Brandenburg SaxonyAnhalt
North Rhine Westphalia
Restaurant clusters
Saxony Thuringia
Hesse Rhineland Palatinate
Czech Republic
Saarland Bavaria
France
BadenWrttemberg
N
Incidence per 100,000 population
100 km
Switzerland
Austria
0.00 0.010.65 0.663.00 3.0130.00
Figure 2. Incidence of the HemolyticUremic Syndrome According to County in Germany. The incidence shown is per 100,000 population. A total of 810 cases have been detected so far in this outbreak. Cases are attributed to a particular county if that county was the probable site of infection.
Incidence (HUS cases/100,000 population)
to 33). Demographic and clinical characteristics at presentation did not differ significantly between patients with diarrhea in whom the hemolyticuremic syndrome developed and those in whom it did not develop (Table 2). An examination of the platelet counts and creatinine and lactate dehydrogenase levels 5 days before through 2 days after the onset of the syndrome in 10 patients with the hemolyticuremic syndrome (Fig. 4) indicates that the development of the hemolyticuremic syndrome was sudden.
Microbiologic Features
3 All HUS cases (20012010) 2 Cases in females (outbreak 2011)
1 Cases in males (outbreak 2011) 0

4 9 4 1 9 20 2 4 25 2 9 30 3 4 35 3 9 40 4 4 45 4 9 50 5 4 55 5 9 60 6 4 65 6 9 7 0
The serotype of the Shiga-toxinproducing E. coli outbreak strain is O104:H4. The strain ferments sorbitol within 24 hours and is lactose-positive, beta-glucuronidasepositive, and subtilase-negative. The strain carries the gene for a Shiga-toxin 2 variant (stx2a). Other typical Shiga-toxinproducing E. coli genes such as stx1, eae, and ehx are missing. In addition, the pathogen possesses genes typical of enteroaggregative E. coli, such as attA, aggR, aap, aggA, aggC, located on a virulence plasmid (heat-stable enterotoxin EAST-1 negative). All outbreak strains are resistant to beta-lactam antibiotics (e.g., ampicillin) and third-generation cephalosporins and are partially resistant to fluoroquinolones (nalidixic acid). The strain is sensitive to carbapenems and ciprofloxacin. The outbreak strains produce an ESBL complex (CTX-M15) and beta-lactamase TEM-1. The National Reference Center has so far typed 439 isolates of this outbreak clone from 650 samples screened in local or regional laboratories for Stx production or presence of stx. Of the 60 isolates that have been analyzed thus far with the use of pulsed-field gel electrophoresis (4 from patients with the hemolyticuremic syndrome and 56 from patients with Shiga-toxinproducing E. coli gastroenteritis), all have had indistinguishable patterns on pulsedfield gel electrophoresis.
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15
Age Group (yr)
Figure 3. Incidence of the HemolyticUremic Syndrome (HUS) in the Outbreak According to Age Group and Sex. A total of 810 cases have been detected so far in this outbreak. The agespecific incidence of all 696 cases of the hemolyticuremic syndrome reported from 2001 through 2010 is shown for comparison.
Discussion
In this preliminary report, we describe the epidemiologic characteristics of a large outbreak of the hemolyticuremic syndrome. There have been more than 800 incident cases of the hemolytic uremic syndrome, predominantly affecting adults, in this outbreak since May 1, 2011. In addition, as of June 17, 2011, as many as 15 other countries, including the United States, have reported
cases occurring among people who had traveled to northern Germany: 41 cases of the hemolytic uremic syndrome (including one death) and 68 cases of Shiga-toxinproducing E. coli gastroenteritis.11 The current outbreak probably began on May 8 or 9; the three cases of the hemolyticuremic syndrome in patients with an onset of gastroenteritis before these dates are atypical for the outbreak. In addition, the patient who had the first case of Shiga-toxinproducing E. coli gastroenteritis with confirmed serotype O104 infection had a disease onset on May 8. To date, there are important differences between this outbreak and previous large outbreaks of Shiga-toxinproducing E. coli infection,12-17 such as the one that occurred in Japan in 1996, in which there were 121 cases of the hemolytic uremic syndrome all in children.12 First, the hemolyticuremic syndrome represents a quarter of the ascertained cases, which is a much larger percentage than in other outbreaks. Second, the majority of the cases of the hemolyticuremic syndrome (approximately 89%) have occurred in adults rather than in children, with the majority occurring in women. Third, the causative agent was a nonO157 Shiga-toxinproducing E. coli strain (O104:H4). The outbreak strain combines the virulence properties of two different diarrhea-causing E. coli pathotypes: typical enteroaggregative E. coli and
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Table 1. Demographic and Clinical Characteristics and Laboratory Test Values of Patients Positive for Shiga-ToxinProducing E. coli at First Presentation.* Variable Total (N = 141) Adults (N = 124) Without HUS Age yr Mean Range Male sex no./total no. (%) Bloody diarrhea no./total no. (%) Abdominal pain no./total no. (%) Nausea no./total no. (%) Vomiting no./total no. (%) Temperature C Hemoglobin g/dl Leukocytes billions/liter Platelets billions/liter Creatinine mg/dl Bilirubin mg/dl Lactate dehydrogenase U/liter C-reactive protein mg/liter 37 287 49/141 (35) 117/131 (89) 33/97 (34) 29/111 (26) 36.70.5 13.52.1 11.54.2 215.488.4 1.41.9 0.90.6 410569 18.230.0 40 2084 14/110 (13) 95/105 (90) 23/77 (30) 14/87 (16) 36.60.5 14.21.4 11.13.5 245.352.5 0.80.2 0.80.5 19695 15.027.0 49 2287 0/11 11/11 (100) 9/11 (82) 4/8 (50) 5/9 (56) 36.90.5 10.82.4 13.27.2 88.392.8 2.61.9 1.90.9 890433 30.232.2 0.02 1.00 0.30 0.30 0.01 0.12 <0.001 0.08 <0.001 <0.001 <0.001 <0.001 0.06 With HUS 0.08 12 217 3/5 (60) 3/5 (60) 5/5 (100) 3/4 (75) 4/5 (80) 36.90.5 14.11.6 13.35.2 297.439.4 0.70.3 0.80.5 23042 46.065.7 11 415 5/11 (45) 6/11 (55) 7/8 (88) 2/5 (40) 5/7 (71) 36.90.3 10.12.1 12.25.8 51.336.7 4.94.8 1.40.8 1835873 19.320.8 1.00 1.00 1.00 0.50 1.00 0.98 0.001 0.73 <0.001 0.08 0.19 0.001 0.20 P Value Children (N = 17) Without HUS With HUS 0.80 P Value
124/136 (91) 101/106 (95)
* Plusminus values are means SD. Data are for patients who presented to the Hamburg University Medical Center between May 19 and June 1, 2011. To covert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. HUS denotes the hemolyticuremic syndrome. P values are for the presence versus the absence of the hemolyticuremic syndrome within subgroups of children and adults.
Shiga-toxinproducing E. coli. It has been speculated that the outbreak strain is a typical enteroaggregative E. coli strain that has acquired the bacteriophage encoding stx2a.18 Enteroaggregative Shiga-toxinproducing E. coli isolated from patients with the hemolyticuremic syndrome have been described previously,19 albeit rarely. A similar Shiga-toxinproducing E. coli O104:H4 strain, with a different set of fimbriae, was isolated in 2001 from two siblings in Germany in whom the hemolyticuremic syndrome had developed.20 Since typical enteroaggregative E. coli are isolated primarily from humans,21 the origin of this outbreak may not be zoonotic. In this outbreak, the proportion of patients with outbreak cases in whom the hemolyticuremic syndrome developed was 25%, despite public advice to patients to seek medical care (and laboratory testing) if they had bloody diarrhea which probably led to a more complete ascertainment of gastroenteritis cases. Similarly, the
hemolyticuremic syndrome developed in 20% of prospectively observed patients with Shiga-toxinproducing E. coli diarrhea at a hospital in Hamburg. These proportions are higher than those in previous outbreaks12-17 and higher than the proportion (6%) ascertained through active surveillance of Shiga-toxinproducing E. coli O157:H7, the virulent prototype of Shiga-toxin producing E. coli, in the United States.22 Taken together, these data suggest that the pathogen in the current outbreak is exceptionally virulent. Of note, the Shiga-toxin variant of the outbreak strain has previously been isolated in Germany only from the rare sorbitol-fermenting Shigatoxinproducing E. coli O157:H, a hypervirulent pathogen in children that is associated with high mortality.23 Another feature of the pathogen is the estimated median incubation period of 8 days for this outbreak, which is longer than the 3-day to 4-day incubation period reported for Shigatoxinproducing E. coli O157:H7.13,24
Table 2. Demographic and Clinical Characteristics of Patients Positive for Shiga-ToxinProducing E. coli (STEC) Who Were Followed Prospectively. Characteristic Age yr Male sex no./total no. (%) Reported fever no./total no. (%) Bloody diarrhea no./total no. (%) Interval between onset of diarrhea and first presentation in STEC unit days Stool frequency no. of stools/day Abdominal pain no./total no. (%) Vomiting no./total no. (%) Previous contact with other patients with STEC no./total no. (%) Total (N = 59) 38.614.0 23/59 (39) 4/55 (7) 48/58 (81) 4.14.7 9.48.9 46/59 (78) 11/59 (19) 13/59 (22) Without HUS (N = 47) 38.513.3 18/47 (38) 4/46 (9) 37/46 (80) 4.05.0 9.99.6 35/47 (74) 7/47 (15) 11/47 (23) With HUS (N = 12) 38.916.8 5/12 (42) 0/9 (0) 10/12 (83) 4.13.3 7.45.4 11/12 (92) 4/12 (33) 2/12 (17) P Value 0.93 0.76 0.12 0.87 0.98 0.47 0.24 0.15 0.80
* Plusminus values are means SD. Data are for patients who were prospectively followed at the Shiga-toxinproducing E. coli (STEC) unit of the Hamburg University Medical Center between May 25 and June 6, 2011. P values are for the presence versus the absence of the hemolyticuremic syndrome.
At present, it remains to be elucidated why women are overrepresented among the cases of the hemolyticuremic syndrome. No sex difference has been observed with respect to the risk of development of the hemolyticuremic syndrome among a limited sample of patients with diarrhea who were prospectively followed at HUMC. Furthermore, it is unclear whether the atypical age distribution of cases in this outbreak primarily reflects the distribution of exposure or is attributable to the specific properties of this outbreak strain or both. The outbreak strain lacks the intestinal adherence factor intimin (encoded by the gene eae), which might be of particular importance for virulence in children. The gene eae is found in the majority of Shiga-toxinproducing E. coli isolated from German children who have gastroenteritis (e.g., 85% of children younger than 3 years of age25) and in 97% of these organisms isolated from children with the hemolyticuremic syndrome in Germany and Austria.26 In contrast, the majority of Shigatoxinproducing E. coli isolated from adults with sporadic cases of gastroenteritis lack eae,25 and eaenegative strains have previously been isolated from adults with the hemolyticuremic syndrome.27 The most common clinical sign in adults was bloody diarrhea accompanied by abdominal cramps. The clinical presentation in adults differed from that in children. Bloody diarrhea occurred significantly more often in adults ir-
respective of the presence or absence of the hemolyticuremic syndrome whereas vomiting was reported more frequently in children. 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 in the case of bloody diarrhea is a subject for further investigation. Clinical symptoms such as abdominal pain, bloody diarrhea, and the frequency of loose stools did not differ between patients in whom the hemolytic uremic syndrome developed and those in whom it did not. Changes in laboratory values, indicating renal failure and hemolysis, occurred quickly, often within 24 hours (Fig. 4). Daily laboratory testing of platelet counts and creatinine and lactate dehydrogenase levels appeared to be pivotal for the early diagnosis of the hemolyticuremic syndrome, and these laboratory tests were more sensitive than were patient-reported symptoms and the physical examination. Indeed, several patients reported that they had begun to recover from bloody diarrhea several days after the initial presentation, at the same time as the onset of the hemolyticuremic syndrome. For many reported cases, information on exact symptoms (e.g., diarrhea or bloody diarrhea) and additional microbiologic information are not yet available. Consequently, although the clinical picture of the hemolyticuremic syndrome in adults appears to be very specific for this outbreak, among the
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A
300
Platelets (billions/liter)
200
100
5 (N= 2)
4 (N= 4)
3 (N= 8)
2 (N= 2)
1 (N= 3)
0 (N= 10)
1 (N= 8)
2 (N= 9)
Days in Relation to HUS Onset
B
3.0
Creatinine (mg/dl)
2.5 2.0 1.5 1.0 0.5 0.0

5 (N= 2) 4 (N= 4) 3 (N= 8) 2 (N= 2) 1 (N= 3) 0 (N= 10) 1 (N= 8) 2 (N= 9)
C
1500
Lactate Dehydrogenase (U/liter)
1000
500
5 (N= 2)
4 (N= 4)
3 (N= 8)
2 (N= 2)
1 (N= 3)
0 (N= 10)
1 (N= 8)
2 (N= 9)
Figure 4. Selected Laboratory Values. Shown are selected laboratory values from up to 10 patients followed prospectively from their first presentation, relative to the onset of the hemolyticuremic syndrome (indicated by the vertical red line). Solid lines represent medians, and dashed lines interquartile ranges. To convert values for creatinine to micromoles per liter, multiply by 88.4.
cases of Shiga-toxinproducing E. coli diarrhea, cases unrelated to this outbreak cannot be efficiently filtered out with the use of serotype information. As of the time of this report, the German outbreak is not over, although case numbers are currently declining. Raw produce or salad condiments are suspected as the food vehicle. Investigations are ongoing.
10
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank the physicians and laboratory personnel, who are working under intense strain and yet are keeping up their notification requirements; local and state health departments for quickly passing on case data to the Robert Koch Institute; and epidemiologists in other countries for providing detailed travel and disease information regarding patients with travel-associated cases.

References
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Notification Database. Berlin: Robert Koch Institute, 2001-2010. 11. EHEC outbreak: update 18. 2011. (http://www.euro.who.int/en/what-we-do/ health-topics/emergencies/internationalhealth-regulations/news/news/2011/06/ ehec-outbreak-update-18.) 12. Fukushima H, Hashizume T, Morita Y, et al. Clinical experiences in Sakai City Hospital during the massive outbreak of enterohemorrhagic Escherichia coli O157 infections in Sakai City, 1996. Pediatr Int 1999;41:213-7. 13. Bell BP, Goldoft M, Griffin PM, et al. A multistate outbreak of Escherichia coli O157:H7-associated bloody diarrhea and hemolytic uremic syndrome from hamburgers: the Washington experience. JAMA 1994;272:1349-53. 14. Guh A, Phan Q, Nelson R, et al. Outbreak of Escherichia coli O157 associated with raw milk, Connecticut, 2008. Clin Infect Dis 2010;51:1411-7. 15. Matsell DG, White CT. An outbreak of diarrhea-associated childhood hemolytic uremic syndrome: the Walkerton epidemic. Kidney Int Suppl 2009;112:S35-7. 16. Soderstrm A, Osterberg P, Lindqvist A, et al. A large Escherichia coli O157 outbreak in Sweden associated with locally produced lettuce. Foodborne Pathog Dis 2008;5:339-49. 17. Wendel AM, Johnson DH, Sharapov U, et al. Multistate outbreak of Escherichia coli O157:H7 infection associated with consumption of packaged spinach, August-September 2006: the Wisconsin investigation. Clin Infect Dis 2009;48:107986. 18. Scheutz F, Mller Nielsen E, FrimodtMller J, et al. Characteristics of the enteroaggregative Shiga toxin/verotoxinproducing Escherichia coli O104:H4 strain causing the outbreak of haemolytic uraemic syndrome in Germany, May to June 2011. Eurosurveillance 2011;16(24): pii=19889. (http://www.eurosurveillance .org/ViewArticle.aspx?ArticleId=19889.) 19. Morabito S, Karch H, Mariani-Kurk-
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Copyright 2011 Massachusetts Medical Society.
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Shiga-ToxinProducing E. coli Outbreak in Germany

Shiga-ToxinProducing E. coli Outbreak in Germany

Date of Disease Onset

Denmark Baltic Sea North Sea

SchleswigHolstein MecklenburgVorpommern Bremen

Lower Saxony Berlin

North Rhine Westphalia

Hesse Rhineland Palatinate

0.00 0.010.65 0.663.00 3.0130.00

Shiga-ToxinProducing E. coli Outbreak in Germany

Incidence (HUS cases/100,000 population)

3 All HUS cases (20012010) 2 Cases in females (outbreak 2011)

1 Cases in males (outbreak 2011) 0

Age Group (yr)

124/136 (91) 101/106 (95)

Shiga-ToxinProducing E. coli Outbreak in Germany

Days in Relation to HUS Onset

2.5 2.0 1.5 1.0 0.5 0.0

Days in Relation to HUS Onset

Lactate Dehydrogenase (U/liter)

Days in Relation to HUS Onset

Shiga-ToxinProducing E. coli Outbreak in Germany

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