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Enteroaggregative E. coli (EAEC) – Disease, Pathogenesis, Treatment, Diagnosis

What is Enteroaggregative E. coli (EAEC)?

  • Enteroaggregative Escherichia coli (EAEC or EAggEC) is a pathotype of Escherichia coli that is responsible for both acute and chronic diarrhea in both developed and developing countries. It can also cause urinary tract infections. EAEC is characterized by its unique “stacked-brick” pattern of adhesion to the human laryngeal epithelial cell line HEp-2. The pathogenesis of EAEC involves the aggregation and adherence of the bacteria to the intestinal mucosa, where they produce enterotoxins and cytotoxins that damage host cells, leading to inflammation and diarrhea.
  • EAEC is considered an emerging enteric pathogen, and it is the second most common cause of traveler’s diarrhea, following Enterotoxigenic E. coli. It is also a frequent cause of diarrhea among pediatric populations. In addition, EAEC has been associated with chronic infections in children and immunocompromised individuals, such as those with HIV infection. The awareness of EAEC increased due to a severe outbreak in Germany in 2011, where over 5000 cases and at least 50 fatalities occurred. The outbreak was caused by an EAEC O104:H4 strain that was infected with a Shiga toxin-encoding phage, typically associated with Shiga toxin-producing E. coli.
  • EAEC strains exhibit genetic heterogeneity, and identifying virulence factors important for pathogenesis has proven challenging. Many EAEC strains encode a transcriptional factor called aggR (aggregative regulator), which belongs to the AraC family of transcription activators. AggR regulates various plasmid and chromosomally encoded virulence factors, including those involved in aggregative adherence fimbriae biogenesis and toxin production. Several toxins, such as ShET1, Pet, and EAST-1, have been associated with EAEC virulence. However, further research is needed to fully understand their role in the pathogenesis of EAEC.
  • EAEC strains are diverse and exhibit autoagglutination in a “stacked-brick” arrangement over the epithelium of the small intestine and, in some cases, the colon. They are characterized as E. coli strains that do not secrete enterotoxins LT or ST and adhere to HEp-2 cells in an AA pattern. The exact prevalence of EAEC-related diseases is unclear due to the lack of a specific molecular marker for these bacteria. The genes encoding adhesins, toxins (including Shiga toxin), and other virulence proteins vary significantly among EAEC strains.
  • Outbreaks of gastroenteritis caused by EAEC have been reported in the United States, Europe, and Japan, indicating its importance as a cause of childhood diarrhea in both developed and developing countries. In recent years, EAEC has received increasing attention as an emerging enteric pathogen, highlighting the need for further research and understanding of this pathotype of Escherichia coli.

Disease Caused by Enteroaggregative E. coli (EAEC)

  • Disease caused by Enteroaggregative Escherichia coli (EAEC) can have significant impacts, particularly in children. EAEC is known to be one of the few bacterial pathogens associated with chronic diarrhea and growth retardation in children.
  • The characteristic feature of EAEC is its plasmid-mediated aggregative adherence, which leads to the formation of a distinctive “stacked brick” pattern of bacterial adhesion. This adherence pattern results in various pathological changes in the intestines. The interaction between EAEC and the intestinal epithelium leads to the shortening of microvilli, which are essential for nutrient absorption. This impairment in microvilli function contributes to decreased fluid absorption in the intestines.
  • The presence of EAEC in the intestines triggers an inflammatory response, characterized by mononuclear infiltration and hemorrhage. The infiltration of mononuclear cells into the intestinal tissue further contributes to the damage caused by EAEC infection. These pathological changes collectively disrupt normal intestinal function, leading to diarrhea.
  • Chronic diarrhea associated with EAEC infection can have long-lasting effects on children, as it can result in malabsorption of nutrients and subsequent growth retardation. The persistent inflammation and damage to the intestinal mucosa can interfere with the absorption of essential nutrients, vitamins, and minerals, hindering proper growth and development.
  • Furthermore, the decreased fluid absorption caused by EAEC can exacerbate the symptoms of diarrhea, leading to dehydration and electrolyte imbalances, especially in young children.
  • Overall, the disease caused by EAEC is characterized by chronic diarrhea, growth retardation in children, shortening of microvilli, mononuclear infiltration, hemorrhage, and decreased fluid absorption. Understanding the pathogenic mechanisms and consequences of EAEC infection is crucial for the development of effective prevention and treatment strategies to mitigate the impact of this pathogen on public health, particularly in pediatric populations.

Pathogenesis Mechanism of Enteroaggregative E. coli (EAEC)

The pathogenesis of Enteroaggregative Escherichia coli (EAEC) involves several stages and mechanisms. EAEC is primarily transmitted through the fecal-oral route, often through contaminated food and water sources.

  • Stage One: The initial stage of EAEC pathogenesis involves the attachment of the bacteria to the intestinal mucosa. This attachment is facilitated by aggregative adherence fimbriae (AAF) and other adhering projections. AAF is composed of three fimbriae, encoded by the pAA plasmid: aag, aafA, and agg-3. aggA is responsible for the aggregative phenotype and haemagglutination of human erythrocytes. aafA enables EAEC to adhere to the intestinal mucosa, while agg-3 acts as an adhesion. Additionally, three-membrane-associated proteins (MAP) play a crucial role in EAEC’s adherence, including haemagglutination of animal cells.
  • Stage Two: Following the initial attachment, EAEC forms a biofilm on the mucosal surface. The production of this biofilm is regulated by a transcriptional factor called AggR and involves the activation of multiple genes. The biofilm formation helps EAEC to establish a stable presence on the mucosa. Interestingly, studies have shown that EAEC can survive within the mucus layer of the intestines. This ability may explain why malnourished children infected with EAEC, living in poor conditions, often develop mucoid stools and experience prolonged episodes of diarrhea.
  • Stage Three: In this stage, EAEC exerts its pathogenic effects through the release of toxins and the elicitation of an inflammatory response. The toxins produced by EAEC are destructive to the intestinal villi and enterocytes. Three toxins have been identified in EAEC: plasmid-encoded toxin (Pet), heat-stable toxin (EAST1), and Shigella enterotoxin 1 (ShET1). These toxins contribute to the cytotoxic effects observed in EAEC infections. They induce mucosal toxicity, inflammatory responses, and intestinal secretion, further exacerbating the damage to the intestinal epithelium.

The pathogenesis of EAEC is a complex process involving bacterial adhesion, biofilm formation, toxin production, and inflammatory responses. Understanding the mechanisms underlying EAEC pathogenesis is crucial for developing effective strategies to prevent and treat infections caused by this pathogen.

At-Risk Populations and Mode of Infection

Enteroaggregative Escherichia coli (EAEC) infections pose a risk to various populations, and the mode of infection primarily involves the consumption of contaminated food and water.

Contaminated food is recognized as the main source of EAEC infection and has been associated with numerous foodborne outbreaks of diarrhea. The presence of EAEC in contaminated food can lead to the transmission of the pathogen to individuals who consume the contaminated food products.

Moreover, the contamination of water sources also plays a significant role in the transmission of EAEC. Consuming water contaminated with EAEC can result in infection and subsequent development of gastrointestinal symptoms.

Certain populations are particularly at risk for EAEC infections:

  1. Children living in areas where EAEC is endemic: EAEC has been linked to persistent diarrhea in children residing in regions where the pathogen is prevalent. In such areas, EAEC infections can contribute to the burden of diarrheal diseases, causing prolonged illness and potential growth retardation in affected children.
  2. Individuals with human immunodeficiency virus (HIV) infection: People living with HIV, particularly those with compromised immune systems, are more susceptible to various infections, including EAEC. EAEC can cause diarrhea in HIV-infected individuals, leading to further complications and potential exacerbation of their underlying condition.
  3. Travelers from industrialized countries visiting less-developed areas: EAEC can act as a causative agent of diarrhea in travelers from industrialized nations who visit less-developed regions of the world. The consumption of contaminated food or water during travel increases the risk of EAEC infection and subsequent gastrointestinal symptoms.

In summary, contaminated food and water are central to the transmission of EAEC. The pathogen is implicated in foodborne outbreaks of diarrhea, emphasizing the importance of proper food handling and hygiene practices. EAEC infections can affect various populations, including children in endemic areas, individuals with HIV infection, and travelers visiting less-developed regions. Understanding the at-risk populations and modes of transmission can help in implementing preventive measures and improving public health strategies to reduce the impact of EAEC infections.

Clinical Presentation of EAEC

The clinical presentation of Enteroaggregative Escherichia coli (EAEC) infection can vary, but it is typically characterized by the following symptoms:

  1. Watery secretory diarrhea, often with inflammatory cells: EAEC infection commonly leads to watery diarrhea, which may be accompanied by the presence of inflammatory cells in the stool. The diarrhea is usually non-bloody but can be mucoidy in some cases.
  2. Low-grade fever: Many individuals with EAEC infection experience a mild elevation in body temperature, presenting as a low-grade fever.
  3. Nausea and vomiting: Nausea and vomiting are common symptoms associated with EAEC infection, although they may not be present in all cases.
  4. Dehydration: The prolonged watery diarrhea caused by EAEC can lead to dehydration, especially if adequate fluid intake is not maintained.
  5. Abdominal pain and cramping: EAEC infection can cause abdominal pain and cramping, which may range from mild discomfort to more severe pain or tenderness in the abdomen.

The clinical course of EAEC infection can vary. In some cases, the symptoms may be self-limiting and resolve within a few days. However, particularly in children and individuals with HIV infection, EAEC infection can progress to persistent diarrhea, lasting for an extended period.

Bloody diarrhea is rare in EAEC infection and is mostly observed in children. However, a hybrid strain of EAEC and Shiga toxin-producing E. coli (STEC) was identified in the 2011 Germany outbreak, which caused bloody diarrhea.

EAEC infection can be acquired through various sources:

  1. Contaminated water: Ground and surface water sources, including streams, lakes, and rivers, may become contaminated with EAEC through human and animal fecal matter. Consumption of contaminated water can lead to infection.
  2. Contaminated food: Consumption of contaminated food is a common route of EAEC infection. Foods such as ground beef, unpasteurized milk, and fresh produce have been associated with EAEC outbreaks.
  3. Improper food handling: Inadequate cooking or handling of food, particularly meats and poultry, can result in EAEC transmission. Cross-contamination from improper cleaning of cooking utensils can also contribute to the spread of the bacteria.
  4. Person-to-person transmission: EAEC can be easily transmitted from infected individuals to others, especially when proper hand hygiene practices are not followed. This mode of transmission is particularly relevant in settings with infected children and adults who may not practice adequate handwashing.

In summary, the clinical presentation of EAEC infection includes watery secretory diarrhea, low-grade fever, nausea, vomiting, dehydration, abdominal pain, and cramping. While bloody diarrhea is rare, persistent diarrhea may occur in children and HIV-infected individuals. Proper food and water hygiene, along with appropriate handwashing practices, are crucial for preventing the transmission of EAEC.

Diagnostic Methods for EAEC

The diagnosis of Enteroaggregative Escherichia coli (EAEC) infection involves specific laboratory techniques aimed at identifying the presence of EAEC in patient samples. The following diagnostic methods are commonly used:

  1. Isolation of E. coli from stool samples: The definitive diagnosis of EAEC infection is made by isolating E. coli strains from the stool samples of patients. Stool cultures are performed to identify and isolate the bacteria responsible for the infection.
  2. HEp-2 assay: The HEp-2 assay is considered the gold standard for detecting EAEC. This assay involves culturing EAEC isolates with human laryngeal epithelial cell line HEp-2. The characteristic feature of EAEC, known as the aggregative adherence (AA) pattern, can be observed in this assay. The AA pattern is characterized by the presence of bacterial clusters arranged in a stacked-brick configuration. The identification of this pattern helps in confirming the presence of EAEC strains.
  3. DNA probe: The plasmids present in most EAEC strains share a high degree of DNA homology. This characteristic allows the use of DNA probes to detect EAEC. The AA probe is a specific DNA sequence derived from the plasmid replicon adjacent to a cryptic open reading frame. A PCR assay utilizing primers designed from the AA probe sequence can be employed to detect the target sequence associated with EAEC.

These diagnostic methods help in confirming the presence of EAEC in patient samples. Isolation of E. coli from stool cultures, visualization of the AA pattern in the HEp-2 assay, and the use of DNA probes provide important tools for accurate identification of EAEC strains.

It is important to note that these diagnostic methods may require specialized laboratory facilities and expertise. Clinicians and healthcare providers should consult with qualified laboratory professionals for accurate testing and interpretation of results.

Additional Tests for EAEC

In addition to the standard diagnostic methods for Enteroaggregative Escherichia coli (EAEC) mentioned earlier, there are additional tests that can aid in the identification and characterization of EAEC strains. These tests include:

  1. Pellicle formation in Mueller-Hinton broth: EAEC probe-positive organisms can display a distinctive pellicle formation when grown in Mueller-Hinton broth. The pellicle refers to a thick biofilm-like layer that forms at the air-liquid interface of the broth culture. This unique growth pattern can be observed visually and may indicate the presence of EAEC.
  2. Polystyrene culture tube or dish assay: This test involves growing EAEC strains in polystyrene culture tubes or dishes at 37°C overnight without shaking. The absence of shaking allows the bacteria to settle and form a bacterial film on the surface of the polystyrene. This film can be easily visualized with staining methods such as Giemsa stain. The presence of a bacterial film suggests aggregative adherence, which is a characteristic feature of EAEC.

These additional tests help provide supplementary evidence for the identification and characterization of EAEC strains. The pellicle formation in Mueller-Hinton broth and the bacterial film formation on polystyrene surfaces are indicative of the aggregative adherence properties of EAEC. Performing these tests can contribute to a more comprehensive understanding of the characteristics and behavior of EAEC strains.

It is worth noting that these additional tests are not typically used as standalone diagnostic methods for EAEC. They are often employed in research settings or specialized laboratories to further investigate the specific properties and behavior of EAEC isolates. Clinical diagnosis and confirmation of EAEC infection primarily rely on the isolation of E. coli from patient samples and the demonstration of the aggregative adherence pattern in the HEp-2 assay, as mentioned earlier.

Management Strategies – Treatment for EAEC

The management strategies for Enteroaggregative Escherichia coli (EAEC) infections focus on supportive care and rehydration. While many EAEC infections are self-limited and resolve on their own, symptomatic cases require appropriate management. Here are the key management strategies for EAEC infections:

  1. Supportive care: Most EAEC infections do not require specific antimicrobial treatment. Instead, the emphasis is on providing supportive care to alleviate symptoms and promote recovery. Rest is important to allow the body to heal, and individuals should ensure an adequate intake of fluids to prevent dehydration.
  2. Rehydration: Patients with profuse diarrhea or vomiting are at risk of dehydration and should be rehydrated promptly. This can be achieved by drinking plenty of water or by using oral rehydration solutions such as Rehydralyte or Pedialyte. These solutions contain a balanced mix of electrolytes and fluids to replace those lost during diarrhea and vomiting.
  3. Antibiotic treatment: In certain cases, when EAEC infection is severe or persists, antibiotics may be considered. Non-Shiga toxin-producing E. coli strains, including EAEC, can be treated with antibiotics such as fluoroquinolones (e.g., ciprofloxacin), macrolides (e.g., azithromycin), and rifaximin. However, the choice of antibiotic may depend on regional susceptibility patterns, as EAEC susceptibility to antibiotics can vary. In many regions, EAEC strains are susceptible to fluoroquinolones and rifaximin. It is important to note that antibiotic treatment is not routinely recommended for all EAEC infections and should be used judiciously based on clinical judgment and local guidelines.
  4. Prevention of transmission: To prevent the spread of EAEC infections, practicing good hygiene and food safety measures are crucial. This includes regular handwashing with soap and water, especially after using the restroom and before handling food. Proper food handling, storage, and cooking techniques are also important in preventing EAEC contamination.

FAQ

What is Enteroaggregative E. coli (EAEC)?

Enteroaggregative E. coli (EAEC or EAggEC) is a pathotype of Escherichia coli that causes acute and chronic diarrhea in both developed and developing countries. It can also cause urinary tract infections.

How is EAEC transmitted?

EAEC is primarily transmitted through the fecal-oral route, often through contaminated food and water sources.

What are the symptoms of EAEC infection?

Symptoms of EAEC infection can include watery secretory diarrhea, low-grade fever, nausea, vomiting, abdominal pain, and dehydration. In some cases, EAEC infection can lead to persistent diarrhea.

How is EAEC diagnosed?

The diagnosis of EAEC infection involves isolating E. coli strains from stool samples and demonstrating the characteristic aggregative adherence (AA) pattern in the HEp-2 assay. Additional tests, such as DNA probes and growth assays, may also be used.

Who is at risk for EAEC infection?

Children living in areas where EAEC is endemic, individuals with HIV infection, and travelers from industrialized countries visiting less-developed areas are considered at higher risk for EAEC infection.

Can EAEC cause chronic diarrhea?

Yes, EAEC has been associated with chronic diarrhea, especially in children and immunocompromised individuals. It can lead to prolonged episodes of diarrhea and growth retardation in affected children.

What is the treatment for EAEC infection?

Most EAEC infections are self-limited and do not require specific antibiotic treatment. Supportive care, including rest and adequate fluid intake, is important. In severe cases or persistent infections, antibiotics such as fluoroquinolones, macrolides, or rifaximin may be considered.

How can EAEC infections be prevented?

Prevention of EAEC infections involves practicing good hygiene, including regular handwashing, especially after using the restroom and before handling food. Proper food handling, storage, and cooking techniques are also important to prevent EAEC contamination.

Are there any outbreaks associated with EAEC?

Yes, there have been reported outbreaks of gastroenteritis caused by EAEC in various regions, including the United States, Europe, and Japan. In particular, a notable outbreak occurred in Germany in 2011, causing thousands of cases and fatalities.

Are all EAEC strains the same?

No, EAEC strains are highly genetically heterogeneous. There is variation in the presence of virulence factors and susceptibility to antibiotics among different EAEC strains.

References

  • Kaur P, Chakraborti A, Asea A. Enteroaggregative Escherichia coli: An Emerging Enteric Food Borne Pathogen. Interdiscip Perspect Infect Dis. 2010;2010:254159. doi: 10.1155/2010/254159. Epub 2010 Mar 11. PMID: 20300577; PMCID: PMC2837894.
  • https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(01)00144-X/fulltext
  • https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/escherichia-coli-diarrheagenic
  • https://intermountainhealthcare.org/-/media/files/health-info/germwatch/gastroenteritis/eaec.pdf?la=en
  • https://www.sciencedirect.com/topics/medicine-and-dentistry/enteroaggregative-escherichia-coli
  • https://www.frontiersin.org/articles/10.3389/fcimb.2018.00306/full
  • https://www.uptodate.com/contents/pathogenic-escherichia-coli-associated-with-diarrhea
  • https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008851
  • https://www.nimml.org/immunology/enteroaggregative-escherichia-coli
  • https://www.efsa.europa.eu/en/efsajournal/pub/4330
  • https://www.mdpi.com/1422-0067/21/24/9543
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  • https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(14)62724-5/fulltext
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