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E. coli Infection and Hemolytic-uremic Syndrome

By Amesh A. Adalja, MD, June 6, 2011

On May 27, 2011, the World Health Organization (WHO) announced that Germany was investigating an unusually large outbreak of hemolytic-uremic syndrome (HUS) that began in approximately the second week of May 2011. The causative agent is an uncommon and especially virulent strain of the bacterium Escherichia coli (E. coli). More than 2,000 cases and 22 deaths have been identified to date in 12 European nations, and 4 imported cases have been identified in the U.S.1,2 Thus far, all cases appear to be connected in northern Germany, but it has proven difficult to trace the definitive source of the contamination with the Shiga toxinproducing E. coli (STEC). Nonetheless, the chief suspects, based on analysis of elements common among case patients, have been raw salad vegetables, including cucumbers, tomatoes, lettuce, and bean sprouts.2-3 See the CDC Health Alert Network alert of June 3, 2011, for additional official information.1

Foodborne Pathogen

Several forms of E.coli can cause foodborne illness, with diarrhea and related symptoms, and many are minor ailments (E.coli is the major pathogen behind traveler’s diarrhea). Gastrointestinal E. coli infections, including those caused by STEC, typically declare themselves after a 1 to 8 day incubation period following exposure; the infections are transmitted via fecal-oral spread.2 A low infectious dose of only 100 organisms is needed to cause disease. Watery and/or bloody diarrhea and cramping abdominal pain are the chief symptoms.

However, not all foodborne E. coli infections are benign. Among the most serious of E. coli infections is that caused by a specific type of the bacterium that possess a Shiga-like toxin that can cause HUS, which is a serious complication that can occur with STEC infections. It occurs in approximately 5%–10% of cases, primarily in children or the elderly. HUS may lead to the need for dialysis and may be fatal.4 This type of E. coli, termed Shiga toxin-producing or verocytoxin-producing E. coli (STEC/VTEC) is responsible for the current large outbreak in Europe. HUS is usually caused by fecal-oral spread of the O157:H7 strain.

HUS is a type of hemolytic anemia characterized by the presence of schistocytes, thrombocytopenia, and azotemia. The kidneys are the most susceptible organ, but any organ, including the brain, eye, and colon, can become ischemic from capillary and larger vessel thrombosis. Complement activation is thought to play a role in the pathogenesis.5 Death or end-stage renal disease occurs in 12%.4

STEC strains contain 2 bacteriophage-produced toxins that act as protein synthesis inhibitors and cause cellular death and the ensuing inflammatory/thrombotic cascade of HUS. The toxins Stx1 and Stx2 are related to the toxin produced by the bacterium Shigella dysenteriae (type I). STEC strains that also have the ability to efface and attach to intestinal cells through the presence of a genetic pathogenicity island are termed Enterohemorrhagic E.coli (EHEC).4

Disease caused by these organisms is not uncommonmany historical cases have been traced to contaminated ground beef productsand a high percentage of cows carry the major culprit bacteria E.coli O157:H7. However, other non-O157 types of E. coli are capable of harboring the toxin as well.4

In the cases in Germany, the O104:H4 type of E. coli has been identified. This strain has been previously identified as a rare cause of STEC/HUS.2

There is some indication that the O104:H4 strain has microbiological characteristics that are distinct from O157:H7 strains. These characteristics, which affect the methods the bacterium employs to attach to intestinal epithelial cells, are similar to some of the attributes of Enteroaggregative E. coli (EAEC) strains, which may explain the greater percentage of HUS seen in this outbreak and its occurrence in older age groups.2

Diagnosis by Stool Culture

The primary means to identify an STEC strain of E. coli is by stool culture. Sorbitol-MacConkey agar is used, but only detects O157:H7 strains. Immunoassays and/or PCR testing will have to be used to identify Shiga toxin production and are essential for laboratory confirmation of non-O157 caused cases.4

Antimicrobials Contraindicated

Unlike many other bacterial diseases, antimicrobial therapy is not beneficial in EHEC/HUS cases. In fact, antimicrobial exposure can enhance the synthesis of toxin and worsen disease. The treatment of these cases should be supportive, with emphasis on fluid resuscitation, avoidance of nephrotoxins (eg, medications or IV contrast), and analgesia. Renal replacement therapy and plasma exchange may be necessary. Antimotility agents to decrease the frequency of stools are also contraindicated.4

Complement-inactivating Monoclonal Antibody Looks Promising

The New England Journal of Medicine recently published a report from a research team that administered the monoclonal antibody eculizumab (Soliris)—which is FDA approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH)—to 2 patients who then had dramatic improvements in their disease course.5 Though this report is preliminary, the use of eculizimab should be further explored for this condition.

No Direct Threat to the U.S.

While this outbreak in Europe does not pose a direct threat to the U.S.—as the U.S. imports less than 0.2% of fresh produce from Germany4—clinicians in this country should be prepared to recognize and institute the correct treatment for imported cases and the unrelated domestic cases that occur. The resolution of the current outbreak of STEC/HUS and the ensuing delineation of the microbiological characteristics of the bacterium and identification of the culprit food item will deepen the understanding of E. coli, provide further information regarding the pathogenicity of STEC strains, and possibly identify areas for improving food safety.

References

  1. CDC Health Alert Network. Health advisory. Notice to Health Care Providers—Shiga Toxinproducing E. coli O104 (STEC O104:H4) Infections in U.S. Travelers Returning from Germany. June 3, 2011. http://www.bt.cdc.gov/HAN/han00322.asp. Accessed June 4, 2011.
  2. EHEC outbreak in Germany. World Health Organization. http://www.euro.who.int/en/what-we-do/health-topics/emergencies/international-health-regulations/ehec-outbreak-in-germany. Accessed June 4, 2011.
  3. Sprouts linked to European E coli outbreak. CIDRAP. June 5, 2011. http://www.cidrap.umn.edu/cidrap/content/fs/food-disease/news/jun0511sprouts.html. Accessed June 6, 2011.
  4. Four US cases may be tied to European E coli outbreak. CIDRAP. June 3, 2011. http://www.cidrap.umn.edu/cidrap/content/fs/food-disease/news/jun0311ecoli.html. Accessed June 4, 2011.
  5. Donnenberg MS. Enterobacteriaceae. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 7th ed. Philadelphia, PA: Churchill Livingstone; 2010.
  6. Lapeyraque A, Malina M, Fremeaux-Bacch V, et al. Complement blockade in severe shiga-toxin–associated HUS. N Engl J Med 2011; [Epub ahead of print]. http://www.nejm.org/doi/full/10.1056/NEJMc1100859. Accessed June 4, 2011.