NORD gratefully acknowledges Bernard S. Kaplan, MB BCh, Division of Pediatric Nephrology, The Children's Hospital of Philadelphia, for assistance in the preparation of this report.
The hemolytic uremic syndrome is defined by the sudden occurrence of acute hemolytic anemia with fragmented red blood cells, low levels of platelets in the blood (thrombocytopenia), and acute kidney injury. Hemolytic uremic syndrome is a general term that covers three main subtypes STEC (typical), atypical hemolytic uremic syndrome, and Sp HUS (Streptococcal pneumonia associated HUS). This report covers STEC (typical) hemolytic uremic syndrome, which is most often associated with E. coli infection and bloody diarrhea. NORD has a separate report on the rarer atypical hemolytic uremic syndrome, which is not caused by infection with E. coli and is often the result of a genetic mutation.
Typical hemolytic uremic syndrome (HUS) is an uncommon disease that occurs in 5 to 15 percent of individuals, especially children, who are infected by the Escherichia coli (E. coli) bacterium, usually O157:H7. This organism releases toxins into the gut that are absorbed into the bloodstream and transported by white blood cells (leukocytes) to the kidneys. This results in acute renal injury. There may also be damage to the brain with seizures and even coma, the pancreas with pancreatitis and occasionally diabetes mellitus, and other organs.
Typical HUS mainly affects young children between one and 10 years. More recently large numbers of adults were affected by STEC HUS in Europe. The onset of HUS is preceded by an illness characterized by vomiting, abdominal pain, fever, and, usually, bloody diarrhea.
The symptoms and severity of typical HUS vary greatly from one person to another. The disorder can be mild or it can progress to cause life-threatening complications. Most children with typical HUS recover without permanent damage; however, about 75 percent recover without complications.
The symptoms of typical HUS are usually preceded by infection of the digestive tract (gastroenteritis) characterized by abdominal cramps and pain, fever and diarrhea. Diarrhea eventually becomes bloody within a few days. Nausea and vomiting also occur in many cases. Approximately three to 10 days after the development of gastroenteritis, additional symptoms appear including sudden onset of paleness (pallor), irritability, weakness, diminished excretion of urine (oliguria) or no urine [anuria], and lack of energy (lethargy). In some cases, seizures also occur during this initial phase.
Some infants may also develop small, unexplained bruises, small red or purple, pinhead-sized spots on the skin or mucous membranes (petechiae), and, rarely, bleeding from the nose or mouth.
More than half of the children with STEC HUS develop impaired kidney (renal) function that may progress to renal failure and require dialysis. STEC HUS is the most common cause of acute renal failure in young children. Renal failure is characterized by an inability of the kidneys to process waste products from the blood and excrete them in the urine, regulate the balance of salt and water in the body, and perform other vital functions. Acute renal failure may result in diminished amounts of urine [oliguria, anuria]; blood in the urine (hematuria); excess levels of protein in the urine (proteinuria), high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); In some cases, acute renal failure may lead to life-threatening complications.
Most individuals with STEC HUS completely recover from renal failure. However, in approximately 10 percent of cases, affected individuals may develop chronic renal failure. This is extremely uncommon after recovery from an episode of STEC HUS. Those who have severe permanent kidney damage with proteinuria, elevated blood pressures and an increase in serum creatinine concentrations may have progressive loss of kidney function approximately five to 10 years after the acute episode. A small percentage of patients will require chronic dialysis and kidney transplantation.
Some individuals with STEC HUS develop symptoms associated with the central nervous system including (as mentioned above) the sudden onset of lethargy and irritability and seizures. Additional CNS symptoms include an impaired ability to control voluntary movements (ataxia), weakness on one side of the body (hemiparesis), confusion, and coma.
The pancreas may become involved in typical HUS. The pancreas is an important organ located behind the stomach that secretes enzymes that aid in digestion. The pancreas also secretes insulin, which helps break down sugar. Pancreatic involvement is usually mild, but fluid accumulation in the pancreas (pseudocysts) and destruction of pancreatic tissue (necrosis) can occur. In about 3 percent of cases, insulin-dependent diabetes can develop. A small number of patients may develop gall bladder stones.
In most cases, typical HUS occurs in association with infection by a particular strain of (E. coli) known as O157:H7. In a recent European outbreak, the strain was O104:H4 and there were 4320 bloody diarrhea cases, 850 cases of HUS and 82 deaths. . The bacterium may reside in the intestinal tract of certain domestic animals, mainly cattle, and may be transmitted to humans through the consumption of unpasteurized milk or infected, undercooked meat or poultry. Cases have been reported in which STEC HUS occurred after the consumption of unpasteurized or otherwise untreated apple juice or cider. Epidemics have followed ingestion of contaminated lettuce, spinach or bean sprouts. It is important to note that transmission may be the result of person-to-person contact within a family or at a kindergarten.
Although most cases of STEC HUS are associated with E. coli infection, other related toxin-producing (i.e., Shiga-producing) bacteria, such as Shigella dysenteriae type I, have also caused STEC HUS.
The O157:H7 strain of E. coli produces a poison known as Shiga toxin or verotoxin that is absorbed through the intestines. Verotoxin damages specific cells (endothelial cells) that line the inner walls of the blood vessels, particularly those of the kidneys. Damage to these blood vessels (microangiopathy) leads to complications such as anemia, thrombocytopenia, acute renal failure, and other symptoms and findings associated with typical HUS. For example, microangiopathic hemolytic anemia occurs when red blood cells are destroyed or damaged as they pass through the small damaged blood vessels. Likewise, circulating platelets are also damaged due to passage through these blood vessels, ultimately resulting in thrombocytopenia and the abnormal accumulation of platelets within narrowed blood vessels, causing the formation of small blood clots (microthrombi). As a result, blood flow to several organs such as the kidneys, brain, and pancreas may be decreased, leading to multiple organ dysfunction or failure.
STEC HUS affects males and females in equal numbers. Some studies have suggested that the disorder affects females more severely than males. It can affect children or adults, but is more common in children under 10, especially children between 7 months and 6 years of age. STEC HUS is the most common cause of acute renal failure in children. STEC HUS is estimated to occur in 1-3 per 100,000 people in the general population. The incidence rate of E. coli infection in North America is estimated to be 8 in 100,000 people in the general population. However, only 5 to 15 percent of individuals infected with E. coli progress to develop STEC HUS.
A diagnosis of STEC HUS may be suspected upon identification of characteristic findings. STEC HUS should be suspected in anyone, especially young children who develop sudden acute renal failure, anemia and thrombocytopenia after an episode of gastroenteritis with blood diarrhea.
The diagnosis of STEC HUS is confirmed by a thorough clinical evaluation, a detailed patient history, and laboratory tests, particularly stool, blood and urine tests. Stool samples may contain Shiga-toxin producing E. Coli. Blood tests may reveal low levels of circulating red blood cells with fragmented cells called schistocytes, and decreased levels of platelets and elevated levels of white blood cells and immature red blood cells (reticulocytes); stool antibodies against shiga toxin: and higher than normal levels of creatine, a waste product of normal muscle breakdown that is excreted by the kidneys. Testing of the urine (urinalysis) will reveal blood (hematuria) and/or protein (proteinuria). The bilirubin levels and liver enzymes may also be elevated.
In some cases, additional diagnostic tests may include microscopic examination of samples of kidney tissue (renal biopsy) and electroencephalography (EEG). Microscopic examination of the kidney glomeruli (organelles) that filter the blood passing through the kidneys may and reveal characteristic changes that occur in STEC HUS such as narrowing of the glomerular capillaries and arterioles, formation of microthrombi, and cell death (necrosis). Renal biopsies are rarely needed in these cases. An EEG may reveal brain wave patterns that are characteristic of certain types of seizure activity.
The treatment of STEC HUS is aimed at managing existing symptoms and preventing further complications. Early diagnosis is essential for appropriate acute, aggressive care. Intravenous volume expansion may decrease the frequency of oligoanuric renal failure in patients with E. coli 0157:H7 gastroenteritis who are at risk for progressing to HUS. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, kidney specialists (nephrologists), intensive care physicians, nurses, nutritionists and social workers need to work in teams to treat patients.
Specific treatment includes control of hypertension and seizures.
Red blood cell transfusions are needed if the hemoglobin concentration falls below 7 gm/dl. Some patients require many blood transfusions. Platelet transfusions are indicated for active bleeding or before surgical procedures.
Monitoring fluid and electrolyte balance is essential to prevent fluid overload and dangerous complications such as elevated potassium and acid levels. In order to maintain proper fluid and electrolyte levels, intravenous fluid and/or nutritional supplementation may be required. In some cases, affected individuals with kidney impairment may require treatment that involves using a special medical procedure to remove wastes from the blood (dialysis) until the kidneys can recover and function on their own.
Most infants and young children with STEC HUS tend to recover with immediate, appropriate, aggressive supportive therapy. Recovery time may be longer in affected adults, since kidney complications tend to be more extensive. Long-term follow-up and observation are usually recommended to monitor for potential chronic kidney disease and hypertension.
Antibiotic therapy for the E. coli gastroenteritis should be avoided in typical HUS because antibiotics may increase the release of toxins into the intestine. However large, randomized clinical trials have not been performed to confirm these findings.
In those cases in which the patient has progressed to end stage renal disease (ESRD), a kidney transplant is performed. ERSD is a condition in which the kidneys permanently fail to work, but rarely occurs in typical HUS. Kidney transplants for children with STEC HUS are successful and the disease almost never recurs.
Plasma exchange, also known as plasmaphersis is usually not used in the treatment of typical HUS. This procedure is a method for removing potentially harmful substances (toxins, metabolic substances, and plasma parts) from the blood. Blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused into the affected individual. This therapy is used more often, without any evidence of efficacy, for adults with STEC HUS.
There is no evidence that medications that suppress the activity of the immune system (immunosuppressive agents) or intravenous immunoglobulins have any value in the treatment of typical HUS.
Corticosteroids, vitamin E, anticoagulants, and drugs that break down clots (fibinolytics) are ineffective in treating individuals with typical HUS.
The value of eculizumab in the treatment of STEC HUS has not been proven.
The outcomes of STEC HUS have improved, and the acute mortality rate in children is 1-4%. About 70% of patients recover completely from the acute episode and the remainder has varying degrees of sequelae. Very few retrospective studies have reviewed these patients over long periods. The kidneys bear the brunt of the long-term damage: proteinuria (15-30% of cases); hypertension (5-15%); chronic kidney disease (CKD) (9-18%); and end stage kidney disease (ESKD) (3%). A small number have extra-renal sequelae such as colonic strictures, cholelithiasis, diabetes mellitus, or brain injury. Most renal sequelae are minor abnormalities such as treatable hypertension and/or variable proteinuria. Most of the patients who progress to ESKD do not recover normal renal function after the acute episode. Length of anuria (more than 10-14 days) and prolonged dialysis are the most important risk factors for a poor acute and long-term renal outcome. After the acute episode all patients must be followed for at least five years, and severely affected patients should be followed indefinitely if there is proteinuria, hypertension or a reduced glomerular filtration rate (GFR).
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