Shiga toxin-producing Escherichia coli (STEC)

Escherichia coli (E. coli) is a large and diverse group of bacteria that normally live in the intestines of humans and animals. Most strains of E. coli are harmless or even beneficial, but some can cause serious illness by producing toxins that damage the cells lining the intestines and other organs. These strains are called Shiga toxin-producing E. coli (STEC) because they produce a type of toxin called Shiga toxin.

Shiga toxin was first discovered in Shigella dysenteriae, a bacterium that causes dysentery, a severe form of diarrhea with blood and mucus in the stool. Shiga toxin is composed of one A subunit and five B subunits, which bind to specific receptors on the surface of host cells. The A subunit then enters the cell and blocks protein synthesis, leading to cell death.

There are many different types of STEC, which are classified by their O and H antigens on their surface. The most common and well-known type is E. coli O157:H7, which was first identified as a cause of human disease in 1982 after an outbreak of bloody diarrhea linked to contaminated hamburgers. However, other types of STEC, such as O26, O45, O103, O111, O121, and O145, can also cause severe illness and are sometimes referred to as non-O157 STEC.

STEC infections can range from mild diarrhea to hemorrhagic colitis (HC), a condition characterized by severe abdominal cramps and bloody diarrhea. In some cases, especially in children under five years of age and the elderly, STEC infections can lead to a life-threatening complication called hemolytic uremic syndrome (HUS), which involves kidney failure, low platelet count, and hemolytic anemia.

STEC infections are usually acquired by eating or drinking contaminated food or water, such as undercooked ground beef, raw milk, unpasteurized juice, or fresh produce. The bacteria can also be transmitted from person to person through poor hygiene or contact with animals or their feces. It takes only a small number of bacteria (less than 100) to cause infection. The symptoms usually appear within 3 to 4 days after exposure but can range from 1 to 10 days.

STEC infections are diagnosed by testing stool samples for the presence of the bacteria or their toxins. Treatment is mainly supportive, as antibiotics are not effective and may increase the risk of HUS. Fluid replacement and electrolyte balance are important to prevent dehydration and complications. In cases of HUS, hospitalization and dialysis may be required.

STEC infections are preventable by following good food safety practices, such as cooking meat thoroughly, washing fruits and vegetables before eating, avoiding raw or unpasteurized dairy products and juices, and washing hands frequently with soap and water.

Shiga toxin-producing Escherichia coli (STEC) can cause a range of diseases in humans, from mild, uncomplicated diarrhea to severe bloody diarrhea and hemolytic uremic syndrome (HUS). HUS is a life-threatening complication that involves kidney failure, low platelet count, and hemolytic anemia.

The severity of the disease depends on several factors, such as the strain of STEC, the amount of bacteria ingested, and the host`s susceptibility. Most cases of STEC infection are caused by E. coli O157:H7, but other serotypes can also produce Shiga toxins and cause disease.

The symptoms of STEC infection usually start 3 to 4 days after exposure to the bacteria but can range from 1 to 10 days. The symptoms include:

• Severe stomach cramps

• Diarrhea (often bloody)

• Vomiting

• Low or no fever

Some people may have mild or no symptoms at all, but they can still spread the infection to others. Most people recover within 5 to 7 days without treatment, but some may develop complications that require medical attention.

HUS is the most serious complication of STEC infection and occurs in about 5 to 10% of infected children under 10 years of age. HUS usually develops about 7 days after the onset of diarrhea, when the diarrhea is improving. HUS can cause:

• Decreased urination

• Swelling of limbs

• High blood pressure

• Jaundice (yellowing of skin and eyes)

• Seizures or other neurological symptoms

• Bleeding into the skin

HUS can lead to permanent kidney damage or death in some cases. HUS requires hospitalization and intensive care, as some patients may need blood transfusions, plasma exchange, or dialysis.

STEC infections can affect anyone, but they are more common and severe in young children, the elderly, and people with weakened immune systems. The highest incidence of STEC disease is observed in the warm months.

The main source of STEC infections is cattle and other ruminants, which carry the bacteria in their intestines without showing any signs of illness. Humans can become infected by consuming foods or drinks contaminated with cattle feces, such as:

• Raw or undercooked ground beef or other meat products

• Raw milk or unpasteurized dairy products

• Contaminated raw vegetables, fruits, or sprouts

• Contaminated water, including drinking water and recreational water

Other sources of STEC infections include contact with infected animals or their environments (e.g., farms, petting zoos, fairs), contact with infected people (especially those with diarrhea), and exposure to contaminated environments (e.g., surfaces, soil, toys).

STEC infections are highly contagious, as ingestion of fewer than 100 bacteria can cause disease. Therefore, it is important to practice good hygiene and food safety measures to prevent the spread of STEC infections.

The main virulence factors of STEC are the Shiga toxins (Stx), which are classified into two types: Stx1 and Stx2. Both toxins are encoded by genes carried by lysogenic bacteriophages that can infect STEC strains. Both toxins have a similar structure, consisting of one A subunit and five B subunits. The B subunits bind to a specific glycolipid receptor on the host cell surface called globotriaosylceramide (Gb3). This receptor is highly expressed in the intestinal villi and renal endothelial cells, which explains the tropism of STEC for these tissues.

After binding, the A subunit is internalized and cleaved into two fragments: A1 and A2. The A1 fragment inhibits protein synthesis by inactivating the 28S rRNA of the 60S ribosomal subunit. This leads to cell death and tissue damage, resulting in bloody diarrhea and hemolytic uremic syndrome (HUS).

STEC strains can produce different variants of Stx1 and Stx2, which differ in their toxicity and immunogenicity. Some studies have suggested that Stx2 is more potent and more associated with HUS than Stx1. Stx2 can also induce the expression of inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, which may enhance the receptor expression and toxin uptake by host cells.

In addition to Shiga toxins, STEC strains can possess other virulence factors that contribute to their pathogenesis. One of them is the locus of enterocyte effacement (LEE), which encodes a type III secretion system that injects effector proteins into host cells. These proteins mediate the formation of attaching and effacing (A/E) lesions on the intestinal epithelium, characterized by the destruction of microvilli and the formation of pedestal-like structures. A/E lesions impair the absorption of nutrients and water, leading to diarrhea. The LEE also encodes intimin, an adhesin that binds to a receptor called Tir (translocated intimin receptor) on the host cell surface. Intimin-Tir interaction stabilizes bacterial attachment and enhances toxin delivery.

Other putative virulence factors of STEC include plasmid-encoded enterohemolysin (EhxA), which causes hemolysis of erythrocytes and cytotoxicity to intestinal epithelial cells; subtilase cytotoxin (SubAB), which cleaves molecular chaperone called BiP and induces endoplasmic reticulum stress and apoptosis; catalase-peroxidase (KatP), which protects STEC from oxidative stress and enhances its survival in the host; and auto agglutinating adhesin (Saa), which mediates bacterial aggregation and biofilm formation.

The pathogenesis of STEC infections is complex and multifactorial, involving the interplay between bacterial virulence factors, host susceptibility factors, and environmental factors. Understanding these mechanisms is essential for developing effective strategies to prevent and treat STEC infections.

STEC infection can cause a spectrum of clinical manifestations, ranging from mild, uncomplicated diarrhea to hemorrhagic colitis (HC) and hemolytic uremic syndrome (HUS). HC is characterized by severe abdominal pain and bloody diarrhea, which usually develops within 2 days of the onset of symptoms. HUS is a life-threatening complication that occurs in 5% to 10% of infected children younger than 10 years and in some adults. HUS is defined by the triad of acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. HUS can also affect other organs, such as the brain, pancreas, liver, and heart.

The incubation period of STEC infection is typically 3 to 4 days but can range from 1 to 10 days. The initial symptoms are usually non-specific, such as diarrhea, abdominal pain, nausea, and vomiting. Fever is generally absent or low-grade. Diarrhea may become bloody within 24 to 48 hours in 30% to 65% of patients, indicating the development of HC. The duration of diarrhea is usually 4 to 10 days but can be longer in some cases.

HUS usually develops after the onset of bloody diarrhea, with a median time of 7 days (range: 1 to 15 days). The signs and symptoms of HUS can vary depending on the severity and extent of organ involvement. The most common features are:

• Decreased urine output or anuria

• Edema of the face and limbs

• Hypertension

• Pallor

• Fatigue

• Irritability

• Bruising or bleeding into the skin

• Jaundice

• Seizures or other neurological symptoms

• Abdominal pain or distension

• Vomiting or diarrhea

The diagnosis of HUS is based on laboratory findings of hemolytic anemia (low hemoglobin level, high lactate dehydrogenase level, low haptoglobin level, and presence of schistocytes on peripheral blood smear), thrombocytopenia (low platelet count), and renal impairment (elevated serum creatinine level and blood urea nitrogen level). Other laboratory tests may show evidence of hemolysis (elevated bilirubin level), inflammation (elevated C-reactive protein level and white blood cell count), coagulation abnormalities (prolonged prothrombin time and activated partial thromboplastin time), electrolyte disturbances (hyponatremia, hyperkalemia, metabolic acidosis), and liver dysfunction (elevated transaminase levels and alkaline phosphatase level).

The prognosis of STEC infection depends on the severity of HC and HUS. Most patients with uncomplicated diarrhea recover without sequelae. However, patients with HC may develop intestinal perforation, toxic megacolon, or bowel ischemia that require surgical intervention. Patients with HUS have a mortality rate of 3% to 5%, and up to 30% may have long-term complications such as chronic renal failure, hypertension, proteinuria, neurologic impairment, or diabetes mellitus. Early recognition and supportive care are essential for improving the outcome of STEC infection.

STEC infection is usually diagnosed by testing a stool sample. Rapid, accurate diagnosis of STEC infection is important because early clinical management decisions can affect patient outcomes, and early detection can help prevent secondary spread. The following methods are commonly used for laboratory identification of STEC:

• Culture: Stool samples are cultured on selective media such as sorbitol MacConkey agar or rainbow agar. EHEC, in contrast to other E. coli, does not ferment sorbitol and produces pale colonies on sorbitol MacConkey agar. O157 strains appear as black colonies on rainbow agar as they are negative for beta-glucuronidase.

• Toxin detection: Stool samples are tested for the presence of Shiga toxins or their genes by various methods such as enzyme immunoassays (EIA), polymerase chain reaction (PCR), or cell culture cytotoxicity assays. Demonstration of cytotoxicity in Vero cell lines is considered the gold standard method.

• Serotyping: Isolates of E. coli are serotyped based on their O (somatic) and H (flagellar) antigens. The most common serotype associated with STEC infection is O157:H7, but other serotypes such as O26, O45, O103, O111, O121, and O145 have also been implicated in outbreaks and sporadic cases.

CDC recommends that all stools submitted for routine testing from patients with acute community-acquired diarrhea (regardless of patient age, season of the year, or presence or absence of blood in the stool) be simultaneously cultured for E. coli O157:H7 and tested with an assay that detects Shiga toxins to detect non-O157 STEC. If Shiga toxin is detected in a specimen, but E. coli O157:H7 is not isolated, additional testing with PCR or culture on selective media can be performed to identify the non-O157 serotype. All STEC isolates should be sent to public health laboratories for confirmation and further characterization.

The treatment for STEC infections is mainly supportive and symptomatic. There is no specific treatment or vaccine that can prevent or cure STEC infections. The following are some of the general principles of treatment for STEC infections:

• Rehydration therapy: Since diarrhea can cause dehydration (loss of water in the body causing weakness or dizziness), drinking plenty of fluids to stay hydrated is important. Oral rehydration solutions (ORS) that contain electrolytes (such as sodium, potassium, and chloride) can help replace the fluids and salts lost due to diarrhea. Intravenous (IV) fluids may be needed for patients who are severely dehydrated or cannot tolerate oral fluids.

• Avoidance of antibiotics: Antibiotics are not recommended for STEC infections, as they may not improve the symptoms and may increase the risk of hemolytic uremic syndrome (HUS), a serious complication that can cause kidney failure and death. Antibiotics may kill the bacteria and release more toxins into the bloodstream, which can damage the blood vessels and organs. Antibiotics may also interfere with the normal gut flora and increase the risk of other infections.

• Avoidance of antidiarrheal agents: Antidiarrheal agents (such as loperamide or diphenoxylate) are not recommended for STEC infections, as they may slow down the clearance of the bacteria and toxins from the gut and worsen the disease. Antidiarrheal agents may also cause adverse effects such as abdominal cramps, nausea, vomiting, constipation, or toxic megacolon (a life-threatening condition where the colon becomes dilated and paralyzed).

• Monitoring and management of complications: Patients with STEC infections should be monitored closely for signs and symptoms of complications, such as HUS, dehydration, electrolyte imbalance, acid-base disturbance, high blood pressure, bleeding, seizures, or neurological problems. If complications occur, they should be managed promptly and appropriately with supportive measures such as blood transfusions, dialysis, antihypertensive drugs, anticonvulsants, or surgery.

The treatment for STEC infections should be individualized based on the patient`s age, medical history, clinical condition, and laboratory results. The treatment should also be guided by the advice of a healthcare provider and public health authorities. The treatment should aim to prevent or minimize the morbidity and mortality associated with STEC infections.

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