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Typical Hemolytic Uremic Syndrome

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

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NORD is very grateful to Bernard S. Kaplan, MB BCh, Division of Pediatric Nephrology, The Children's Hospital of Philadelphia, for assistance in the preparation of this report.

Synonyms of Typical Hemolytic Uremic Syndrome

Disorder Subdivisions

General Discussion

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.

Symptoms

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.

Causes

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.

Affected Populations

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.

Related Disorders

Symptoms of the following disorders can be similar to those of STEC HUS. Comparisons may be useful for a differential diagnosis.

Atypical hemolytic uremic syndrome (aHUS) is an extremely rare disease characterized by hemolytic anemia, low platelet count (thrombocytopenia) and acute renal failure. It is a distinctly different illness from STEC hemolytic uremic syndrome and is not caused by E. coli producing Shiga toxins. Most cases of aHUS are the result of a genetic disorder that results in abnormalities of inhibitors of the alternative pathway of complement. Atypical hemolytic uremic syndrome may become chronic and patients with aHUS may experience repeated attacks of the disorder. Patients with STEC HUS usually recover from the life-threatening initial episode and usually respond well to supportive treatment. Patients with aHUS are much more likely to develop chronic serious complications such as kidney failure and severe high blood pressure. The new agent eculizumab dramatically improves the outcomes of these patients. (For more information on this disorder, choose "atypical hemolytic uremic" as your search term in the Rare Disease Database.)

Streptococcal pneumoniae associated HUS [SpHUS] is defined by the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in a patient a Streptococcal pneumoniae (S. pneumoniae infection). SpHUS accounts for 5-15% of all cases of HUS. The majority of have pneumonia and a low mortality rate in contrast to those with meningitis who have a more severe clinical course with a mortality rate of 2-12%. SpHUS often may not be diagnosed because of overlapping features with disseminated intravascular coagulation (DIC) and the lack of strict diagnostic criteria. The epidemiology of SpHUS has changed with the emergence of different pneumococcal serotypes as newer vaccines are introduced.

Thrombotic thrombocytopenia purpura (TTP) is a rare blood disorder characterized by the development of blood clots in small blood vessels (thrombotic microangiopathy). There is considerable overlap between the physical findings of this disorder and those associated with typical HUS, but there is irrefutable evidence that they are different disorders with variable, yet overlapping findings due to microangiopathy. Typical HUS most commonly occurs in children, while TTP occurs most often in females in the third or fourth decade of life. Findings may include low levels of platelets in the blood (thrombocytopenia), a diminished number of circulating red blood cells (microangiopathic hemolytic anemia), and/or neurological abnormalities. Thrombocytopenia is associated with a variety of symptoms including the development of purple bruises on the skin, hematuria, and/or small red or purple spots on the skin and/or mucous membranes (petechiae). Neurological abnormalities may include disorientation, headaches, visual abnormalities, seizures, paralysis (paresis), and/or, in severe cases, coma. In addition, affected individuals may also experience fever, fatigue, weakness, abdominal pain, and/or diarrhea. In some cases, individuals with TTP may have acute renal injury, which may result in diminished excretion of urine; blood appearing in the urine (hematuria); high blood pressure (hypertension); an abnormal accumulation of fluid between layers of tissue under the skin (edema); and/or unusually low water content in the body (dehydration). In some cases, acute renal failure may lead to life-threatening complications. The cause of TTP is not known. (For more information on this disorder, choose "Thrombotic Thrombocytopenia Purpura" as your search term in the Rare Disease Database.)

Standard Therapies

Diagnosis
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.

Treatment
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.

Investigational Therapies

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.

Long-term outcomes:
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).

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Typical Hemolytic Uremic Syndrome Resources

Organizations:

References

JOURNAL ARTICLES
Kaplan BS, Ruebner RL, Copelovitch L. An evaluation of the results of eculizumab treatment of atypical hemolytic uremic syndrome. Expert Opinion on Orphan Drugs [in press 2013]
Spinale, JM, Ruebner RL, Copelovitch L, Kaplan BS: Long-term outcomes of shiga-toxin hemolytic uremic syndrome [STEC HUS]. Pediatric Nephrology [in press 2013]

Caletti MG, Missoni M, Vezzani C, Grignoli M, et al. Effect of diet, enalapril, or losartan in
post-diarrheal hemolytic uremic syndrome nephropathy. Pediatr Nephrol 2011;26:1247-1254.

Frank C, Werber D, Cramer JP, et al. Epidemic profile of Shiga-toxin-producing EscherichiacoliO104:H4 outbreak in Germany. N Engl J Med. 2011;365(19):1771-80.

Hickey CA, Beattie TJ, Cowieson J, et al. Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome. Arch Pediatr Adolesc Med. 2011;165(10):884-9.

Copelovitch L, Kaplan BS. Streptococcus pneumoniae--associated hemolytic uremic syndrome: classification and the emergence of serotype 19A. Pediatrics. 2010 Jan;125(1):e174.

Nathanson S, Kwon T, Elmaleh M, Charbit M, et al. (2010) Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 2010;5:1218-1228.

Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of Shiga-toxin-associated hemlotyic uremic syndrome (HUS). Pediatr Nephrol. 2008;23:1749-1760.

Siegler R, Oakes R. Hemolytic uremic syndrome: pathogenesis, treatment and outcome. Curr Opin Pediatr. 2005;17:200-204.

Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;19-25;365(9464):1073-86.

Van Dyck M, Proesmans W. Renoprotection by ACE inhibitors after severe hemolytic uremic syndrome. Pediatr Nephrol. 2004;19:688-690.

Gianviti A, Tozzi AE, De Petris L, Caprioli A, et al. (2003) Risk factors for poor renal prognosis in children with hemolytic uremic syndrome. Pediatr Nephrol 2003;18:1229-1235.

Kaplan, B.S., Meyers, K.W., Schulman, S.L.: The Pathogenesis and Treatment of hemolytic uremic syndrome. Journal of the American Society of Nephrology. 1998; 9:1126-1133.

INTERNET
National Institute of Neurological Disorders and Stoke. Hemolytic Uremic Syndrome in Children.April 12, 2012. Available at: http://kidney.niddk.nih.gov/kudiseases/pubs/childkidneydiseases/hemolytic_uremic_syndrome/ Accessed:January 29, 2013.

Mayo Clinic for Medical Education and Research. Hemolytic Uremic Syndrome (HUS). Dec 18, 2010. Available at: http://www.mayoclinic.com/health/hemolytic-uremic-syndrome/DS00876 Accessed:January 29, 2013.

Parmar MS. Hemolytic Uremic Syndrome. Emedicine Journal. August 6, 2010. Available at: http://emedicine.medscape.com/article/201181-overview Accessed: January 29, 2013.

Gillespie, RS. Pediatric Hemolytic Uremic Syndrome. Emedicine Journal. September 26, 2011. Available at: http://emedicine.medscape.com/article/982025-overview Accessed:January 29, 2013.

Report last updated: 2013/02/07 00:00:00 GMT+0