EHEC A04.3

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 26.03.2021

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History
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In 1885, Theodor Escherich described the bacterium later named after him as the first specific intestinal bacterium. EHEG was first described in 1977.

Definition
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EHEC is the acronym for "Enterohaemorrhagic Escherichia (E.) coli". Escherichia coli (E. coli for short) - also known as coliform bacteria - is a gram-negative, sporeless, acid-forming and peritrichous flagellated and therefore mobile bacterium. It ferments with gas formation, glucose, lactose, mannitol and forms indole. Escherichia coli is normally found in the human and animal intestines. Within the family Enterobaceriaceae in the order Enterobacteriales, E. coli belongs to the important genus Escherichia and is its type species. E.coli plays a major role in intestinal and extraintestinal infections (Hof H et al. 2019)

Enterohemorrhagic Escherichia (E.) coli are coliform bacteria occurring worldwide that have a basic property of producing certain cytotoxins called Shiga toxins - Stx (synonyms: Shiga-like toxins - SLT, Verotoxins - VT). These toxin-producing E. coli bacteria are summarized under the term shigatoxin- or verotoxin-producing E. coli (STEC or VTEC).

Shigatoxins bind to special cell membrane receptors, especially in the capillary endothelium, block protein synthesis there and lead to the rapid death of these afflicted cells. In addition, many EHEC possess a so-called pathogenicity island (LEE - locus of enterocyte effacement), which is responsible for a type III secretion apparatus. This device allows EHEC to deliver cytotoxic or inhibitory toxins directly into the target cell, as if with a hypodermic needle. This can lead to further clinically pathogenic effects, thereby increasing the virulence of EHEC.

The key feature of this type III secretion apparatus is the eae gene. Its gene product, the protein intimin, enables the pathogen to adhere closely to intestinal epithelial cells, among other things.

EHEC that do not possess the eae gene can form other adherence systems with an analogous effect. In addition to their particular virulence, EHEC have a relatively high environmental stability and good survivability in acidic environments.

Occurrence/Epidemiology
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Incidence in Central Europe approx. 1:100,000/year. 2011 Epidemic in Germany with the aggressive serotype O104:H4.

The most significant EHEC serogroup worldwide is O157. This also applies to Germany. Other frequently isolated serogroups are O26, O91, O103 and O145. New serogroups or serovars (classification according to O and H antigens, e.g. O157:H7) are still being identified in connection with human EHEC infections.

Manifestation
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E. coli infections can occur in people at any age. Severe infections occur more frequently in children and older people (Robert Koch Institute 2018).

EHEC infections occur worldwide. The incidence of transmitted EHEC infections is highest in children under 5 years of age (see Epidemiological Bulletin and current Infektionsepidemiologisches Jahrbuch of the Robert Koch Institute - www.rki.de/jahrbuch). Direct contact with a ruminant (cattle, sheep or goats) seems to be the highest risk of disease. Other risk factors are the consumption of raw milk and the presence of diarrhoea in family members. In children > nine years of age and adults, on the other hand, the disease is probably primarily foodborne, with consumption of lamb and of spreadable raw sausages (onion mettwurst, spreadable mettwurst, teewurst) in particular being at increased risk of disease.

Reservoir: Ruminants, especially cattle, sheep and goats, but also wild ruminants (e.g. roe deer and deer) are considered to be an important reservoir and main source of infection of EHEC in humans. Occasionally, other farm animals as well as pets have been shown to excrete EHEC. However, the importance of non-ruminants for the spread of the pathogen and for infections in humans is considered to be low.

Route of infection: EHEC infections can be transmitted in a variety of ways. This always involves unintentional oral ingestion of faecal traces, such as contact with ruminants or consumption of contaminated food. Otherwise, the usual mode of spread of E.coli bacteria is given. Important: Favored by the very low infectious dose of EHEC (< 100 pathogens for EHEC O157), human-to-human transmissions (unlike other bacterial gastroenteritis pathogens) are also a significant route of transmission. In the US, for example, > 50% of outbreaks were foodborne, and ground beef (e.g., in hamburgers) was the most commonly identified food. However, other foods such as salami, Mettwurst, raw milk, unpasteurized apple juice, and green leafy vegetables (e.g., sprouts, spinach, leafy lettuces) consumed raw were also responsible for outbreaks, as shown by epidemiological and microbiological investigations.

Incubationperiod: The incubation period is about 2 to 10 days (average 3 to 4 days). These findings are mainly based on studies on EHEC of serogroup O157. Symptoms of EHEC-associated HUS illness begin approximately 7 days (5 to 12 days) after the onset of diarrhea.

Duration of infectiousness: As long as EHEC bacteria are excreted in the stool, human-to-human transmission is possible in principle. Data on the average duration of bacterial excretion are only available for serogroup O157 and vary considerably from a few days to several weeks. In general, the pathogen can be detected in the stool of children longer than in adults. An excretion period of more than one month with a clinically inconspicuous picture must therefore be expected. The EHEC concentration in the stool decreases with the duration of excretion, so that the risk of transmission also decreases significantly.

Clinical picture
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Diarrhoea: EHEC infections may be clinically inapparent and thus remain undetected. The majority of manifestations of the disease present as bloodless, mostly watery diarrhoea. Accompanying symptoms are nausea, vomiting and increasing abdominal pain, rarely fever.

Haemorrhagic colitis: In 10-20% of patients a severe form of haemorrhagic colitis develops with cramping abdominal pain, bloody stools and sometimes fever.

HUS: Infants, small children, old people and immunocompromised persons are more often severely ill. The most feared is HUS, which occurs mainly in children and is characterized by the triad of hemolytic anemia, thrombocytopenia, and renal failure to the point of anuria. This severe complication occurs in about 5-10% of symptomatic EHEC infections and is the most common cause of acute renal failure in children. This often results in short-term dialysis requirement, more rarely in irreversible renal function loss with chronic dialysis. In the acute phase, the lethality of HUS is about 2%.

Diagnosis
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EHEC infection should be considered in the differential diagnosis of any acute gastroenteritis in childhood. This also applies, irrespective of age, to outbreaks of gastroenteritis (two or more diseases in which an epidemiological link is probable or suspected). In the following situations, there is always an indication for microbiological testing of a stool sample for EHEC:

Diarrhoea + any of the following conditions:

  • children hospitalised for diarrhoea up to 6 years of age
  • visible blood in the stool
  • endoscopically proven haemorrhagic colitis

Patient is directly involved in the production, treatment or marketing of foodstuffs or works in kitchens of restaurants or other facilities with/for communal catering (§ 42 para. 1 no. 3 lit. a and b IfSG)

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Recommendations for laboratory diagnostics of EHEC infections: The most important diagnostic feature is the detection of the shiga toxins or the toxin genes stx1 and/or stx2. Toxin detection should be performed by PCR (conventional or RT-PCR) from colony washout or stool enrichment; PCR assays should be used that allow differentiation of stx1 and stx2. toxin detection should be performed by ELISA (EIA) from E. coli culture (detection of shiga toxin by ELISA directly from stool is too unspecific). Further characterisation of the pathogens by serotyping and/or genome sequencing is desirable for epidemiological questions, especially for outbreak detection. Therefore, pathogen isolation should be attempted and the isolate sent to one of the specialized laboratories listed below. In the case of HUS, the serum should also be tested for LPS antibodies against E. coli O157 and others.

Therapy
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Treatment of the symptoms of the disease is symptomatic. Antibiotic therapy may prolong bacterial excretion and lead to stimulation of toxin formation (see below E.coli) and is therefore indicated only rarely and under certain conditions. In the presence of HUS, forced diuresis and, in the case of global renal insufficiency, haemo- or peritoneal dialysis are usually used. In atypical courses (especially with extrarenal manifestations of HUS), plasma therapy is recommended. In patients in whom von Willebrand factor-cleaving protease ADAMTS13 (VWF-CP) is decreased or in whom antibodies to VWF-CP are present, immunosuppressive therapy is recommended. The treatment should be carried out in specialized centers.

Prophylaxis
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Note(s)
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Historically, those STEC (shiga toxin-producing E. coli) that were capable of causing severe illness (haemorrhagic colitis and haemolytic uraemic syndrome - HUS) were referred to as EHEC. In the last two decades, however, a large number of different STEC strains have been isolated even from patients with mild gastroenteritic symptoms, so that in the Infection Protection Act (IfSG) the term EHEC is used to refer to those STEC that are capable of causing symptoms of disease in humans and are thus human pathogens. Based on their antigenic structure, they belong to different serogroups (classification according to surface O antigens) (RKI 2018).

There are two types of shiga toxins encoded at different gene loci (stx1 gene and stx2 gene). The stx genes can be further subdivided into subtypes (stx1a to stx1c and stx2a to stx2i). Severe diseases, in particular bloody diarrhoea and complications such as haemolytic uraemic syndrome (HUS), are almost exclusively caused by stx2-positive EHEC strains of the subtype stx2a and, more rarely, stx2c or stx2d.

Literature
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  3. Hof H et al (2019) Escherichia. In: Hof H, Schlüter D, Dörries R, eds Duale Reihe Medizinische Mikrobiologie. 7th, completely revised and expanded edition. Stuttgart: Thieme pp 410-414
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Last updated on: 26.03.2021