Enterohemorrhagic Escherichia coli

Etiology

The infections caused by E. coli O157:H7 range from asymptomatic to severe. Few individuals can develop potentially fatal complications like hemolytic uremic syndrome (HUS). Chronic renal pathology may persist at times among those that survive. Humans are known to acquire E. coli O157:H7 in multiple ways, for example, contaminated food and water and direct contact with infected animals and humans. Consumption of contaminated food like ground beef, dairy products, and fresh produce is responsible for the majority of the outbreaks. [2]

Cattle are considered as the principal reservoirs for E.coli O157:H7; contamination takes place through their use as food, their manure used as a fertilizer, and through water supplies contaminated by runoff from cattle farms. Although variation has been reported in fecal shedding of E. coli O157:H7 has been ranging from 0 to 80% among the cattle population, a seasonal pattern has also been shown, with prevalence increasing during summer months. Elevated temperature in summers might be responsible for favoring bacterial proliferation and survival.

Epidemiology

The Centers for Disease Control and Prevention (CDC) estimated that foodborne E. coli O157:H7 is responsible for over 63,000 illnesses per year that leads to more than 2100 hospitalizations and deaths in the United States. The economic burden of illness due to this bacteria resulting from medical expenses and death and loss of productivity is estimated to be $405 million per year. [3][4]

According to the 10 US sites of the Foodborne Diseases Active Surveillance Network (FoodNet) preliminary report of 2017, STEC was listed as one of the 9 pathogens commonly transmitted by food. As compared to the incidence 2014 through 2016 the incidence in 2017 was 28% higher. Fifty-seven cases of HUS were identified in 2016; the incidence was not significantly different from 2013 through 2015.

In Norway, HUS was labeled as the second most common cause of acute kidney infection (AKI) in children with an estimated average annual incidence of 0.5 cases per 100,000 children.

Pathophysiology

On entry, EHEC strains produce Shiga-like toxins (Stx) which mediate the dysregulation of membrane ion channels in the epithelial membrane of the intestine that leads to loss of ions and a massive amount of water. This toxin also acts as a cell transduction and immune modulator leading to pro-inflammatory and pro-apoptotic sequela. Endothelial lesions in the microvasculature of the kidney and less frequently of other organs are found to be responsible for sequela of the hemolytic uremic syndrome. The kidney and gastrointestinal (GI) tract are the most commonly affected organs in HUS, but evidence of central nervous system (CNS), pancreatic, skeletal, and myocardial involvement has also been shown in the studies conducted. The mechanism of this microvascular injury is unknown, but evidence shows that verocytotoxin plays a role in mediating cell injury with a resultant change in the normal anti-coagulant profile of the endothelial cell to a procoagulant state. [5] 

After E. coli infection, several factors determine the progression of the disease to HUS like:

1. Bacterial strain: Serotype O157:H7 is most often found to be responsible
2. Age: The rate of progression to HUS is higher in young children. A study showed it to be 12.9% in children younger than 5 years of age, 6.8% in children between 5 to 10 years, 8% in children older than 10 years of age.
3. Antibiotic: Treatment with antibiotic therapy for E. coli O157:H7 has shown to increase the risk of HUS
4. Environmental and genetic factors

Histopathology

In the acute phase of HUS, specimens of the kidney show microvascular injury characterized by deposition of microthrombi along with detached and swollen glomerular endothelial cells associated with infiltration of inflammatory cells. Similar changes have been described in other organs. This shows that HUS is a multisystem disease characterized by endothelial cell injury. [6]

Toxicokinetics

Enterohemorrhagic E. coli is not invasive, making bacteremia rare. It adheres to mammalian cells, secreting bacterial proteins into host cells through a type III secretion system. Ribosome-inactivating Shiga-like toxins (Stx1 and Stx2) are secreted which are responsible for organ damage. Stx 2 has been found to be more often associated with severe disease. Shiga toxin consists of 2 subunits: A and B. Proteolysis further degrades subunit A into A1 and A2. In target organs, for example, the kidney, brain, and gut, subunit B attaches to glycolipid receptors on the cell surface. In humans, these receptors have been identified as Gb3 which are mainly expressed in kidney tubular cells, brain, and gut epithelium. The cytotoxicity is further amplified in the kidney due to the interplay of tumor necrosis factor-alpha. After it binds to the cell surface, Shiga toxin is endocytosed and transported to the Golgi apparatus and endoplasmic reticulum in a retrograde direction from there it is then translocated to the cytosol where it inactivates ribosomes and causes cell death. [5][7]

History and Physical

EHEC clinically manifests as bloody diarrhea (visibly bloody stool specimen) without fever and usually a white blood cell count above 10,000/microL at times associated with abdominal pain. The incubation period between exposure to EHEC and onset of symptoms is typically 3 to 4 days. [8][3][7]

HUS is a major complication of EHEC infection. It is a clinical triad of anemia secondary to hemolysis, impaired renal function, and thrombocytopenia mainly affecting young children. HUS following bloody diarrhea secondary to EHEC is called D+ HUS or typical HUS; whereas, HUS caused by other causes is referred to as D- HUS or atypical HUS.

Evaluation

Patients suspected of infection from EHEC are tested for Shiga toxin or EHEC by doing stool culture. Blood tests and urine tests are also conducted in patients presenting with HUS which can show low red blood cell and platelet count and assess renal functions respectively. [9]

Treatment / Management

Supportive treatment is provided to those having EHEC diarrhea.[5]

Electrolytes and water deficiency should be replaced, especially in patients with D+ HUS. The current advancements in dialysis and intensive care have reduced mortality, mainly in young children. The best option for children is peritoneal dialysis. Bilateral nephrectomy is life-saving and can control the spread of microvascular lesions when the kidneys are the main site of the disease involvement especially in cases of therapy-resistant malignant hypertension.[5] Because the prognosis is often severe, immediate supportive treatment may improve the outcome. Other supportive treatments available for patients with HUS are mainly dependent on their symptoms and mainly include: 

• Red blood cell transfusions
• Platelet transfusions
• Plasma exchange

In general, the prevention of foodborne diseases must be based on good hygienic practices and control of the contamination of foods by biological and chemical hazards. This can be achieved most effectively through the application of food safety assurance programs. Vaccines for EHEC are under study but have not been approved by FDA yet.

Differential Diagnosis

In all patients with HUS symptoms, Shiga toxin/STEC should be tested along with ADAMTS13 activity as clinical presentation, and the organ involvement in hemolytic uremic syndrome and thrombotic thrombocytopenic purpura can overlap. In patients of unusual age or in whom diarrhea is absent anomalous or atypical E. coli, HUS is a possible diagnosis. [5]

Prognosis

Diagnosing EHEC infection early and starting prompt fluid replacement has shown to improve long-term outcomes by reducing damage to the kidney. Advancement in dialysis therapy and improved care of critically ill children have resulted in a significant reduction in acute mortality of HUS to such an extent that chronic complications in long-term survivors are becoming more apparent. [10]

Complications

Often, EHEC associated with bloody diarrhea can resolve without any long-term consequences. The prognosis is severe mainly in patients developing HUS. After being treated for HUS, some children can never recover renal functions and thus require long-term replacement therapies for renal functions whereas those who recover renal functions are at risk of late development of renal disease. Some children may have residual extrarenal problems including neurological defects, insulin-dependent diabetes mellitus, pancreatic insufficiency, or gastrointestinal complications. HUS is thus a disease with substantial mortality and multisystem morbidity. This shows that importance should be given to extra-renal manifestations in the acute phase and renal functions should be monitored in long-term follow-up of HUS patients. [11]