1. Hemolytic uremic syndrome : Shiga-Toxin–Producing Escherichia coli O104:H4 Outbreak in Germany 2011. 9. 7 N Engl J Med 2011;365:709-17 Seo Mi Seon

2. Introduction  HUS (hemolytic–uremic syndrome)  first described in children in the 1950s  Triad : acute renal failure hemolytic anemia thrombocytopenia

3. 1. Microangiopathic hemolytic anemia (MAHA)  hallmark of disorder, major diagnostic criterion  nonimmune hemolysis (ie, negative direct antiglobulin test)  prominent red cell fragmentation (schistocytes) (PB smear)  Serum indirect bilirubin ↑, serum haptoglobin ↓, serum LDH ↑ Peripheral blood smear multiple helmet cells (small black) fragmented red cells (large black) microspherocytes (blue arrows) platelet number is reduced large platelet in the center (red) thrombocytopenia d/t enhanced destruction

4. 2. Thrombocytopenia  mean platelet count : 25,300/microL (range: 5 to 120,000/microL)  less severe in patients who present with renal failure 3. Renal disease  due to a renal thrombotic microangiopathy  Urinalysis : near normal only mild proteinuria (usually 1 - 2 g/day) few cells or casts multiple intracapillary glomerular thrombi

5.  diarrhea-associated HUS primarily in children cause : Shiga-toxin–producing Escherichia coli (serotype O157:H7) usual reservoir : ruminants (cattle) human infection : inadvertent ingestion of fecal matter ex) contaminated food or water contact with animals or farm environment 2’ through contact with infected humans rare event in adults ex) 1989 – 2006 only 21/322 adults (7%) listed in the Oklahoma registry as TTP or HUS with bloody diarrhea

6.  the Robert Koch Institute (Germany’s national-level public health authority)  2011. 5. 19 three cases of the HUS in children admitted to the university hospital in the city of Hamburg  the case numbers were continuing to rise also in adults other areas of Germany (esp. northern Germany)  investigation of the outbreak was initiated to identify the causative agent and the vehicle of infection

7. descriptive epidemiologic, clinical, and microbiologic information on this unusual outbreak NEJM 2011. 6

8. Methods  data from reports of STEC gastroenteritis and HUS  clinical information on patients presenting to Hamburg University Medical Center  outbreak case : reported case of HUS or of gastroenteritis infected by Shiga-toxin–producing E. coli, serogroup O104, serogroup unknown, onset of disease on or after May 1, 2011 in Germany

9.  German Surveillance System  the German Protection against Infection Act of 2001 : detection of a Shiga toxin (Stx) in E. coli isolates or detection of encoding gene (stx) in stool enrichment culture or isolates → must be reported by diagnosing laboratories to local health departments

10.  The German case definition of Shigatoxin–producing E. coli gastroenteritis (without HUS) ≥ 1 : diarrhea (3 ≥ loose stools /24hr) abdominal cramps vomiting  The German case definition of HUS : thrombocytopenia (PLT <150,000 per cubic millimeter) hemolytic anemia acute renal dysfunction ≥ 1 ↑ serum creatinine level (unspecified) oliguria anuria proteinuria hematuria

11.  Reported cases (HUS or STEC) → investigated and recorded by local health department → forwarded Electronically state to the federal  all health departments to immediately forward all case reports  Case details are to be added to the record by local health departments in the future

12. Epidemiologic Curve of the Outbreak 2011.5.1 - 6.18 HUS 810, (fatal case : 27,3.3%) STEC 2412 (fatal case : 12, 0.5%) HUS 25.1% Results - Outbreak Cases

13. Incidence of the Hemolytic–Uremic Syndrome According to County in Germany all 16 states in Germany the “northern Germany outbreak area” - northern states of Hamburg (10.1 cases per 100,000 population) - Schleswig–Holstein (6.7 cases per 100,000) - Bremen (2.7 cases per100,000) - Mecklenburg–Vorpommern (2.2 cases per 100,000) - Lower Saxony (1.7 per 100,000) Most of the cases from other states can be linked to travel-related exposures in the northern Germany outbreak area two satellite clusters linked to restaurants - eastern North Rhine–Westphalia - southern Hesse the area with high incidences (4 to 30 cases per 100,000 population) - centered around the city of Hamburg

14. Incidence of the HUS in the Outbreak According to Age Group and Sex 89% - adults(>17yrs) ≤ 17yrs – median age 11.5 yrs 1% - < 5yrs Median age – 43yrs Female > male (44 vs 41) Hamburg – 34yrs HUS,died – 74yrs (24-91) STEC,died – 83yrs (38-89)

15.  HUS 68%, died 77.8% - female STEC 58 %, died 58.8% - female  Disease onset in june – male 47.8%  Disease onset in may – male 31.9% (P = 0.04)  the five most northern and most affected states 74.3% in Hamburg -female 65.5% in the surrounding states - female (nonsignificant difference)  median incubation period : 8 days (43 case)  onset of diarrhea – dx of HUS : 5 days (79 case)

16. Clinical Information 88% Women :66% 50% : girls 59%96% 89%92% 69%20% 22 (16%) : HUS

17. 13544%20%

18. Selected Laboratory Values

19.  Microbiologic Features  STEC outbreak strain serotype - O104:H4  carries the gene for a Shiga-toxin 2 variant (stx2a)  resistant to beta-lactam antibiotics (e.g., ampicillin) and third-generation cephalosporins  partially resistant to fluoroquinolones (nalidixic acid)  sensitive to carbapenems and ciprofloxacin  produce an ESBL complex (CTX-M15) and beta-lactamase TEM-1

20. Conclusions & Discussion  epidemiologic characteristics of a large outbreak of HUS : > 800 HUS, adults, 2011.5.1 – 2011.6.17  15 countries have reported cases occurring among people who had traveled to northern Germany : 41 HUS, 68 STEC

21.  differences between this outbreak & previous outbreaks (STEC) : in Japan in 1996, 121 HUS 1. 25% HUS : vs STEC O157:H7 → 6% HUS exceptionally virulent incubation period 8days vs 3-4 days 2. 89% adults (women) : lacks the intestinal adherence factor intimin (encoded by the gene eae) particular importance for virulence in children 3. non–O157 Shiga-toxin–producing E. Coli strain (O104:H4)