Typical Hemolytic Uremic Syndrome (HUS)
A thirteen-month old infant presented with classical hemolytic- uremic syndrome (HUS), but with negative cultures for Escherichia coli (E. coli) 0157:H7. HUS is commonly linked to infection with E. coli 0157:H7; however, traditional culture has demonstrated poor sensitivity. Pathogenesis of the organism in HUS involves the production of a Shiga-like toxin (STX), resulting in a triad of symptoms. An early and accurate differential diagnosis, based on patient presentation with acute renal failure, hemolytic anemia, and thrombocytopenia, is critical for supportive treatment and improved prognosis. Patient prognosis is related to the duration of renal failure and dialysis treatment. Research is aimed at improved detection of E. coli 0157:H7 or the STX produced, and future vaccination to eliminate typical HUS.
ABBREVIATIONS: CDC = Centers for Disease Control and Prevention; HUS = hemolytic-uremic syndrome; STX = shiga-like toxin; TTP = thrombotic thrombocytopenic purpura.
INDEX TERMS: hemolytic-uremic syndrome.
Clin Lab Sci 2005:18(2):90
In January, a thirteen-month-old Caucasian male presented with progressive diarrhea over a period of two weeks. During this time, medical attention was sought, and the infant was diagnosed with a common childhood diarrhea, suspected to be due to a rotavirus. However, the infant continued with progressive diarrhea and began showing signs of pallor, dehydration, petechiae on his thighs, and decreased appetite. The infant began experiencing episodes of acute abdominal pain with intermittent periods of lethargy. As the diarrhea worsened, one sixteenth of a tablet of Imodium was given to the infant and he was brought to the local emergency department (ED).
The infant presented in the ED with signs of edema in the extremities from oliguria and acute renal failure. He was catheterized, treated with Lasix to stimulate kidney function, and given nutritional IV support. Vitals revealed hypertension with a blood pressure of 132/55 (normal blood pressure of a 1-year-old Caucasian male is 102/57) and a temperature of 103.5 F. As a result, the infant was given Hydralazine and Tylenol to reduce his elevated blood pressure and temperature respectively.
The initial laboratory results indicated a diagnostic triad of thrombocytopenia, hemolytic anemia, and acute renal failure (Table 1). Subsequently, the infant was diagnosed with hemolytic-uremic syndrome (HUS). Also, it is important to note that the infant’s increased white cell count and fever supported the diagnosis of the onset of the inflammatory reaction that occurs in typical HUS, with E. coli 0157:H7 suspected as the cause.
QUESTIONS TO BE CONSIDERED
* What is the typical presentation of HUS and the patient population at risk?
* What is the pathogenesis and pathophysiology of typical HUS?
* What is the differential diagnosis of typical HUS?
* What is the treatment and long-term prognosis of typical HUS?
* What are preventive measures that can be taken to protect children from HUS?
INTRODUCTION TO HUS
The syndrome now known as HUS, was described in 1955 by Gasser. In 1982, Riley isolated pathogenic Shiga-like toxin producing E. coli (STEC) serotype 0157:H7 from contaminated hamburger. Then, Karmali linked HUS to E. coli 0157: H7 in 1985. Connection of E. coli 0157:H7 to HUS was a major breakthrough in differentiating the mechanisms of the often-confused conditions of thrombotic thrombocytopenic purpura (TTP) and HUS. HUS is currently accepted as the most common cause of acute renal failure in children in the U.S. and is primarily caused by E. coli 0157:H7. The Centers for Disease Control and Prevention (CDC) estimate that with 73,000 E. coli 0157:H7 infections per year in the U.S., 2% to 7% of E. coli 0157:H7 infections result in HUS with the majority of cases occurring in Caucasians less than five years of age.1 The elderly, adults, and older children have higher mortality rates from HUS than occur in younger children.2,3 Interestingly, HUS caused by infection with E. coli 0157: H7 is less common in African-Americans.4 Overall, E. coli 0157:H7 infections costs about 60 lives and $660 million dollars each year, and is now an endemic cause of HUS in the U.S.1,5,6
Table 1. Initial laboratory testing of patient on day 1 of hospitalization
Classical HUS is defined as a thrombotic microangiopathy with a diagnostic triad of acute hemolytic anemia with schistocytes, thrombocytopenia, and acute renal failure. However, classical HUS does not always present with a complete diagnostic triad. A major indicator of typical HUS from E. coli 0157:H7 is presentation with a one to eight day acute gastroenteritis prodrome and bloody diarrhea, unless the infection is acquired by a urinary tract infection or a respiratory infection.7,8 The kidney is the major organ target in classical HUS, but other organs such as pancreas, heart, lungs, and brain may also be involved.9-12 Other factors supportive of a diagnosis of HUS due to E. coli 0157: H7 include its predominance in the summer months and its potential to occur in outbreaks.
HUS, as noted by its name, is merely a syndrome, and therefore, has many known etiologies. Typical (infectious) HUS is caused by bacterial and viral infections such as E. coli 0157:H7, some non- 0157 E. coli strains, Shigella dysenteriae 1, Streptococcus pneumoniae, Salmonella, typhi, Campylobacter jejuni, and HIV. Non- infectious, atypical HUS may be secondary to (but not limited to) pregnancy and postpartum, organ transplant, glomerulonephritis, systemic lupus erythematosus, or treatment with drug therapies such as tacrolimus (FK506), quinine, and mitomycin. However, it is estimated in the U.S. that 90% of cases of HUS in children are primary infections caused by E. coli 0157:H7 with increasing findings of non-0157:H7 E. coli cases, which may cause higher incidences of HUS in other countries.13,14
Infection with E. coli 0157:H7 can be acquired from several sources. Enterohemorrhagic E. coli (EHEC) is carried asymptomatically in the intestines of cattle, where Globotriaosylceramide (Gb^sub 3^) receptors are found throughout the intestinal tract, but cattle lack Gb^sub 3^ receptors in the vasculature.15,16 These findings may play a significant role in colonization. However, the reason cattle are asymptomatic carriers of E. coli 0157:H7 is still being studied. During slaughter, the surface of EHEC contaminated meat is ground into and spread throughout the hamburger. Only 50 to 100 viable organisms of E. coli 0157:H7 are required to cause infection.7 Other food products, besides ground beef, that can be a reservoir for EHEC after contamination with cattle feces include: unpasteurized milk products, apple juice, water, and vegetables. There is seasonality to the shedding of EHEC from cattle, where there is an increased amount of organism shed in the summer months, which correlates with an increase in products with fecal contamination, E. coli 0157:H7 infections, and HUS in the warmer season.17 The infant in the case study, however, presented with HUS in January.
Although cattle are the major source of E. coli 0157:H7, it has been found in other animals, e.g., sheep, goats, deer, and even a small percentage in cats, dogs, horses, and flies.18,19 E. coli 0157:H7 has been shown to survive ten months or longer in contaminated sources that resulted in human infection.20 Additionally, E. coli 0157:H7 can readily be transmitted from person to person, causing concern to families, nursing homes, daycare facilities, and other crowded living conditions.21,22 After September 11, 2001, E. coli 0157:H7 was considered to be a potential agent of bioterrorism.23 In the case of this thirteen-month old child, no other children or adults with whom he had contact were infected.
Pathogenesis and pathophysiology
The pathogenesis of typical HUS begins with the hardiness of E. coli 0157:H7. E, coli 0157:H7 can easily live through freezing at – 80 C for as long as nine months. Its acid resistance increases survival in acidic foods (conditions that are normally used to preserve food from bacterial contamination) because acidity decreases the nutritional competition with other non-acid-resistant organisms. E. coli 0157:H7 can remain viable in a pH environment less than 2.5.24
Once E. coli 0157:H7 enters the body orally, it survives the pH of the stomach, and colonizes in the mucosa of the colon. The exact mechanism of E. coli 0157:H7 pathogenicity is under extensive research. A proposed mechanism is that the lipopolysaccharide and STX from the organism are responsible for activating the phosphatidylinositol cascade, increasing mobilized ionized calcium that allows adherence of the organism to the epithelial cells of the colon and promotes lesion formation. Lesions change the permeability of the epithelial cell membrane to water and electrolytes, causing the prodromal diarrhea, and initiate an inflammatory response partially responsible for the microangiopathic thrombosis.25 The inflammatory response activates neutrophils that release cytokines, platelet activating factor (PAF), and tissue necrosis factor alpha. These play a role in increasing activated neutrophils (leukocytosis), platelet aggregation,26 and up-regulating Globotriaosylceramide (Gb^sub 3^) receptors on kidney and brain endothelial cells,12 respectively. Close proximity of the injured epithelial cells t\o microvasculature results in hemorrhagic colitis (HC) and bloody diarrhea in the typical HUS.
STX access to circulation following HC allows for direct and indirect mechanisms of pathogenicity. STX reaches the kidney and brain through the circulatory system on the surface of platelets, neutrophils, and monocytes.27-29 STX bound to platelets induces platelet aggregation directly, and STX prevents apoptosis in neutrophils, resulting in leukocytosis and increased inflammation.27,30
The proposed primary target of STX from the circulation is the distal convoluted tubular epithelium in children (Gb^sub 3^ receptors may not be present in adults).31 The injured renal epithelial cells also initiate an inflammatory response and release endothelin, tissue plasminogen activator inhibitor-1 (PAI-1), and PAF. Endothelin increases production of PAF, white blood cell activation that results in leukocytosis, and may somewhat increase blood pressure early on in typical HUS. PAI-1 inhibits fibrinolysis of microvascular thrombosis. PAF-activated platelets release thromboxane hence promoting platelet aggregation by vasoconstriction- induced high shear stress. Thromboxane is regulated by prostacyclin released from injured epithelial cells through negative feedback. However, in typical HUS, platelet activation outnumbers production of prostacyclin resulting in thrombosis.32
Microvascular endothelial cells that have Gb^sub 3^ receptors (in children and adults), particularly those of the glomerulus, are extremely sensitive to STX. Injury to the endothelial cells by bound STX is key to the pathogenesis of typical HUS.7,32 STX causes extensive microangiopathic thrombosis, hypoxia, and ischemia in the glomerular endothelial cells, and similar damage can be found in the cerebral endothelial cells of the blood-brain barrier.33 Injury to the endothelial cells is marked by elevated thrombomodulin levels. Lesions from STX involve the glomerular capillaries; thickening of the capillary wall near the glomerulus decreases the glomerular filtration rate.34 Both ischemia and thickened capillaries elevate blood pressure. Progressive damage to the kidneys occurs via hyperfiltration of the functional nephrons that remain after the acute phase.35 Damage to cerebral endothelial cells causes encephalophy, coma, stroke, and cerebral infarcts.33
Toxins are freely permeable to the glomerulus, and the large capillary surface area enhances toxin pathogenicity. The concentration of toxin is increased by countercurrent roles of vasculature and tubules in the kidney.36 STX has one enzymatic subunit A and five receptor-specific B subunits. Subunit A invades and kills the renal endothelial cells by endocytosis and inhibiting translation. Subunit B activates neutrophils, releasing proteases and hydrogen peroxide that irreversibly damage renal cells.37 Oxidative substances and fibrin-platelet aggregations occluding the microvasculature fragment red cells, producing schistocytes on the peripheral blood smear.
It is critical to differentiate typical HUS from atypical HUS, thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIG) for both treatment and prognosis (Table 2). For example, typical HUS requires supportive therapy while TTP mandates plasma exchanges and possibly immunosuppressive treatment with glucocorticoids. Misdiagnosis could be life threatening; a significant number of deaths from TTP occur within forty-eight hours of presentation.38
Atypical causes of HUS are associated with a high mortality rate and recurrences. These causes include complement deficiency involvement, neurological involvement, an inborn error in the metabolism of cobalamin, or a factor H deficiency. Most secondary causes of atypical HUS can be ruled out with patient history. Generally, atypical HUS does not present with leukocytosis or GI prodrome and bloody diarrhea, and is seen more frequently in adults than young children, perhaps simply because adults are likely to have secondary causes.
Table 2. Differential diagnosis of typical HUS including patient case study results
TTP, a completely separate disease from HUS, is the result of a decreased level of von Willebrand Factor (vWF) -cleaving enzyme (ADAMTS-13) due to a deficiency of ADAMTS-13 or antibodies against it.39,40 The classical presentation of TTP includes fever, central nervous system involvement, and the diagnostic triad seen in classical HUS. However, 25% of typical HUS cases have nervous system involvement and many present with fever.41 Unlike typical HUS, TTP does not generally involve gastrointestinal inflammation, or leukocytosis.42 TTP is usually systemic with severe thrombocytopenia resulting in platelet counts below 20 10^sup 9^/L, where typical HUS is primarily localized to the kidney with platelet counts between 30 10^sup 9^/L and 150 10^sup 9^/L. Risk for TTP is not targeted to a specific age group, like typical HUS. In the future, differentiating TTP from HUS may be easier by measuring the functional ADAMTS-13 level in the plasma.43
DIC is a systemic activation of both the coagulation cascade and fibrinolysis, and is commonly associated with pregnancy-related complications like atypical HUS. The easiest most reliable way to differentiate DIC is with routine coagulation testing. Prothrombin time (PT), partial thromboplastin time (PTT), and D-dimer levels are abnormal in DIC, but are normal in patients with typical and atypical HUS. However, vitamin K deficiency may prolong the PT, and D-dimer levels may be elevated with a high concentration of fibrin in the microangiopathic thrombus in patients with typical HUS.44
LABORATORY FINDINGS AND CLINICAL COURSE
Upon diagnosis, the thirteen-monthold infant was transferred via ambulance to a major referral childrens hospital. Albumin, total bilirubin, and hemoglobin from the initial laboratory tests (Table 1) were near normal supporting the beginning of the acute phase of HUS. Hemoglobin drops as hemolysis increases during the acute phase, and total bilirubin rises as hemoglobin from lysed red cells is broken down, following degradation of the hemoglobin porphyrin ring. A type and screen (T&S) and. indirect Coombs were ordered for type- specific supportive transfusions. The indirect Coombs was negative, supporting a non-immune-mediated cause of hemolysis. Clinically, hemolysis is monitored by the hemoglobin level, but LDH and AST tests supplement evaluation of hemolysis. LDH is more specific to hemolysis; however, extremely elevated LDH also reflects tissue necrosis (Table 3).45 Since there is extensive red cell destruction in HUS, most of the haptoglobin is bound to free hemoglobin, giving lower detectable levels of haptoglobin in the serum. Coagulation studies were found to be normal ruling out DIC in the differential diagnosis (Table 3).
Recovery of a small urine sample was obtained from the Foley catheter of the infant for urinalysis (Table 4) which confirmed proteinuria, acidosis, and hemolysis. Red cell casts were not found in this sample, but are commonly found with careful examination in patients with typical HUS.46 The infant began peritoneal dialysis on day 3 (Figures 1, 2, and 3), was given nasogastric tube feedings for nutritional support, and was placed in barrier isolation to prevent transmission of suspected E. coli 0157:H7.
In addition to the urinalysis, stool cultures were ordered for growth of E. coli 0157:H7, Shigella, Yersinia, Salmonella, and Campylobacter. Cultures are done to confirm a causative agent of HUS and for epidemologic purposes such as tracking of the contaminated food product and disease control. Sorbitol MacConkey agar is generally the medium of choice for isolating the non-sorbitol- fermenting E. coli 0157:H7. Most non-pathogenic E. coli found in the normal flora of the GI tract ferment sorbitol. After successive negative stool cultures for STX-producing organisms, the infant was released from barrier isolation. A negative culture does not rule out a typical HUS diagnosis, and is commonly seen due to the transient shedding of E. coli 0157:H7, culturing too late in the course of the infection, or poor culture sensitivities. The best time to obtain a positive culture for the infectious organism is during the GI prodrome.14
Table 3. Laboratory evaluation of patient hemolysis and confirmation of typical HUS
Throughout the infant’s 32-day hospitalization, HUS was monitored with daily basic metabolic panels and cell blood counts. Monitoring hemoglobin, platelets, creatinine, and albumin throughout the acute phase of HUS is indicative of severity and duration of hemolysis, microthrombi, and kidney dysfunction, respectively. An increase in catabolism, during the acute phase of the infection, and the change in distribution of volume to albumin in the serum resulted in hypoalbuminemia, reaching a low of 1.7 mg/dL. Because no platelets were transfused or any other therapy given that would directly affect the platelet count, the rise in platelet count on day-11 marked the initiation of the recovery phase (Figure 2). Day-15 marked the end of the acute phase of the illness with stabilization of the platelet count, hemoglobin, and creatinine (Figures 1-3). After day-15, supportive transfusions were no longer necessary, and on day-20, recovery was confirmed by discontinuation of dialysis with continued stabilization of creatinine levels (Figure 3).
Table 4. Patient urinalysis results on day-2 of hospitalization
As commonly seen in classical typical HUS, the WBC differentials showed a left shift with few myelocytes and metamyelocytes along with leukocytosis and thrombocytopenia. Cell morphology included moderate hypochromic, microcytic red cells with a few schistocytes, nucleated red cells, ovalocytes, polychromasia, and giant platelets. Reticulocyte counts would likely be increased, while the infant attempted to compensate for the anemia with increasedred cell production. A bone marrow aspirate is certainly not necessary and would be risky given the presence of thrombocytopenia. However, cellular morphology of the bone marrow would be expected to show normal to increased megakaryocytes (depending on platelet consumption), and erythroid hyperplasia.
Figure 1. Hemoglobin vs. Time
Figure 2. Platelet Count vs. Time
Figure 3. Creatinine vs. Time
As often occurs with HUS, this infant had several complications. On day2, the infant developed tachycardia, cardiac arrythmia, and periorbital edema. Cardiac arrhythmias in HUS are due to cardiac ischemia, which can also result in myocardial infarction in typical HUS.10 On day-4, slight involvement of the pancreas was seen with elevated serum lipase (Table 3). Both lipase and amylase are markers for pancreatitis. Since lipase is not elevated by as many conditions as amylase, it is a more specific indicator for pancreatitis. After the onset of abdominal pain, lipase levels rose within 12 hours and rapidly fell to normal range within a few days. In addition, the infant developed peritonitis when the dialysis catheter was compromised, which was reflected by the increasing creatinine levels at day-9 (Figure 3). A dialysate culture revealed coagulasenegative StaphyIococcus sp. and Streptococcus pyogenes, and a dialysate sample revealed a neutrophil count of 1830 10^sup 9^/L with 75% neutrophils and 23% monocytes with toxic granulation. The infant was treated with vancomycin and serum levels were monitored. On day-25, the infant spiked a fever of 103 F and was treated with cefotaxime and vancomycin for possible septicemia. Both blood and urine cultures were obtained, and both were found to be negative for growth.
After conclusion of the acute phase, a urinalysis still showed significant proteinuria along with a few granular casts and renal epithelial cells, but the hemoglobin levels and red cell numbers supported the cessation of hemolysis. The infant was discharged on day-32 with resolution of the fever and the acute phase of typical HUS, The infant continues to be closely monitored for long-term prognosis.
The treatment regimen used in the acute phase of typical HUS is primarily supportive and may include medication to control blood pressure, continuous peritoneal dialysis or hemodialysis, packed red cell transfusions, fluid restriction, diuretics, and very careful maintenance of electrolytes. In rare cases, a kidney transplant may be required. Untreated typical HUS will lead to coma, cerebral infarcts, pancreatic insufficiency, and death.46 However, rigorous management of treatment has decreased the mortality rate of typical HUS from 50% to about 5% to 10% throughout the last five decades.47,48
There are important contraindications to certain treatments when typical HUS is diagnosed. Platelets are generally not transfused, because they may cause more severe microangiopathic thrombosis. Antibiotics are also not suggested, because killing E. coli 0157:H7 may rupture the organism’s cell wall, thereby increasing the amount of toxin released, and contributing to the severity of the acute phase.49 If complications occur, however, during typical HUS, such as peritonitis or sepsis, antibiotics may be necessary. Anti- motility drugs for diarrhea are not advised, because they may increase the risk of typical HUS by extending the exposure time of STX to the patient’s cells.50
Long-term treatment for patients requires monitoring of blood pressure, creatinine, and urinalysis.51 Patients exhibiting hypertension and proteinuria are treated to lower the blood pressure with an angiotensinogen-converting enzyme (ACE) inhibitor (blocking the production of renin and consequently, aldosterone) to reduce further damage to the glomerulus, reduce proteinuria, and delay or prevent future chronic renal failure.52 Two years of post-HUS laboratory testing on this infant confirmed hypertension and proteinuria. After beginning treatment with an ACE inhibitor, the infant showed a decrease in blood pressure and proteinuria.
Although prognosis of HUS remains variable, a recent metaanalysis produced significant data. It is estimated that 58% of HUS patients fully recover, 5% die within the acute phase, 11 % develop chronic renal failure or die within four years of the acute phase, and 17% experience long-term residual effects such as hypertension, proteinuria, and a decreased glomerular filtration rate. There is often a period of perceived renal recovery before the onset of long- term residual effects. Surprisingly, even some patients who presented with mild HUS (without dialysis or abnormal urine output) developed renal sequelae.47 Renal sequelae may result in renal failure more than twenty years after the acute phase of HUS.53 Thus, it is extremely important that the renal function of any child with a history of HUS be followed for life.
The best practical indicator of prognosis is the duration of oliguria or anuria and consequently, the need for dialysis during the acute phase of HUS.54 The most sensitive indicator is a kidney biopsy, which shows the degree of renal cortical necrosis. This procedure is impractical and contraindicated in the acute phase, but it is used later to assess long-term prognosis.53,55 Other factors that may support poor long-term prognosis include: elevated white cell count >20 10^sup 9^/L, neural involvement, post-HUS proteinuria, and hypertension during the acute phase.35,56-58 In the case history of the thirteen month old infant, the following poor prognostic indicators were found: oliguria/anuria > 10 days, leukocytosis >20 10^sup 9^/L, post-HUS proteinuria, and hypertension at onset of HUS.
There are three important levels of prevention when dealing with E. colt 0157:H7. On the public level, proper handwashing and safe preparation of food remain the best practices for the prevention of typical HUS. However, too much responsibility has been placed on the public.59 The state and federal government play critical roles in prevention. They are responsible for keeping the food supply safe and ensuring quality assurance by mandating effective screening of food products for E. coli 0157:H7 and other foodborne pathogens. In the past, only a few states required such screening. With the new rapid STX detection methods available, surveillance of E. coli 0157:H7 in the beef industry is improving.60 The Food and Drug Administration has approved the irradiation of ground beef, which can kill at least 90% of E. coli 0157:H7 contaminants.24 A law mandating irradiation of other potentially contaminated food products was approved by the United States Department of Agriculture and is being implemented. cases involving contaminated water sources have also called attention to enforcing regulations for protecting small water systems that in the past received little attention.61
RESEARCH AND THE FUTURE
Current research is aimed at faster and more reliable testing of STX as well as countering the action of STX produced by any organism. The conventional method involving the culture of stool on MacConkey-Sorbitol agar for E. coli 0157:H7 is only 40% sensitive and takes up to three days to complete.62 Further complicating the diagnosis of typical HUS is the usual delay of symptoms for one to two weeks after infection, leaving few organisms in the stool for detection. In addition, more than 100 other shiga toxin-producing E. coli (STEC) serotypes are left undetectable by many clinical laboratories because they ferment sorbitol, like normal intestinal strains of E. coli.63
Improved technology is strongly needed to enhance the sensitivity of culture for E. coli 0157:H7 in HUS patients. In 1996, research showed a success rate of 90% for E. coli 0157:H7 if an immunomagnetic separation (IMS) technique was used to isolate the 0157 antigen (using beads with the corresponding antibody) after use of a pre-enrichment culture medium. This method proved to have many advantages over new PCR methods for detecting E. coli 0157: H7 including at least a 100-fold increase in sensitivity, and less complex testing.64 In 1999, the United States Department of Agriculture began implementing IMS to improve the screening of ground beef. To date, many clinical laboratories have not adopted the improved methods for routine screening of E. coli 0157: H7 in children suspected of HUS.65 If a clinical laboratory is unable to implement new technology for detecting E. coli 0157:H7 and/or STX, the specimen should be referred to an appropriate reference laboratory.
Alternative rapid tests for non-0157 STEC are directed toward the detection of STX produced instead of the organism. One method uses an EIA technology that requires approximately 18 hours to perform (this includes a 16-hour incubation period for increased sensitivity), while another method is a simple toxin detection tests that only takes three hours to perform. Both methods may significantly shorten the time for diagnosis. In addition, other improved methods include PCR followed by pulse-field gel electrophoresis, impedance technology, and enzyme-linked immunoassays.
Vaccination is another potential area of interest. Healthy persons develop an antibody to the antigenic subunit B of STX after exposure.66 When mice were immunized with the B subunit of STX, they were able to produce antibodies that neutralized the potent effects of STX.67 Monkeys have also been successfully immunized and protected by an STX vaccine when challenged with a lethal dosage.68’69 Immunizations may be administered for both humans and cattle in order to reduce E. coli 0157:H7 infections and incidence of typical HUS.
Treatment of patients with monoclonal antibodies, currently in clinical trials, may neutralize the STX in patients presenting with early diagnosis of typical HUS. The monoclonal STX antibody binds STX in the intestine and may render the toxin less able gain accessto the circulation. Hence, STX is less likely to affect the kidney or other organs.42 One remaining concern with this treatment is the remaining lipopolysaccharide (LPS) of the bacteria that also plays an antigenic role in typical HUS, perhaps warranting the need for treatment with another monoclonal specific antibody or a polyvalent antibody to both STX and LPS.32
As in the case of this thirteen-month-old infant with HUS, it is estimated that E. coli 0157:H7 causes 73,000 of the 76 million food- borne illnesses each year. Most food-borne illnesses in the U.S. are self-limiting, but those that cause HUS may lead to death or life- long consequences such as renal sequelae and gastrointestinal complications. Progress has been made in the elimination of food- borne causes of typical HUS via irradiation of food products and improved quality assurance and control in the food industry. Current research is focused on vaccination, improved diagnostic testing methods, and intervening treatments with early diagnosis. “So HUSH all you children and don’t you cry, together we will beat the bug they call E. coli.”70
Clinical Laboratory Science Announces 2004 Distinguished Author Award Recipients
Recipients of the Clinical Laboratory Science (Clin Lab Sci) Distinguished Author Awards are chosen by Clin Lab Sci readers and editorial board members. Nominations are based upon originality, quality of writing, and relevance and value to the clinical laboratory science profession. The Editorial Board of Clin Lab Sci is pleased to announce the following recipients of the 2004 Distinguished Author Awards:
Reports and Reviews
Vicky A LeGrys, Katherine Hartmann, and Joan R Walsh for their article The Clinical Consequences and Diagnosis of Hypothyroidism published in the Fall 2004 issue of Clinical Laboratory Science.
Isaac D Montoya for his article Topography as a Contextual Variable in Infectious Disease Transmission published in the Spring 2004 issue of Clinical Laboratory Science.
Louann W Lawrence for her article Refractory Anemia and the Myelodysplastic Syndromes published in the Summer 2004 issue of Clinical Laboratory Science.
The peer-reviewed Research and Reports Section seeks to publish reports of original research related to the clinical laboratory or one or more subspecialties, as well as information on important clinical laboratory-related topics such as technological, clinical, and experimental advances and innovations. Literature reviews are also included. Direct all inquiries to David G Fowler PhD CLS(NCA), Clin Lab Sd Research and Reports Editor, Dept of Clinical Laboratory Sciences, University of Mississippi Medical Center, 2500 North State St, Jackson MS 39216. (601) 984-6309, (601) 815-1717 (fax). email@example.com
1. Centers for Disease Control and Prevention. Escherichia coli 0157: H7. Available at: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/ escherichiacoli_g.htm Accessed April 28, 2004.
2. Carter AO, Borczyk AA, Carlson JA, and others. A severe outbreak of Escherichia coli 0157:H7 – associated hemorrhagic colitis in a nursing home. N Engl J Med 1987;317:01496-500.
3. Melnyk AMS, Solez K, Kjellstrand CM. Adult hemolytic-uremic syndrome: a review of 37 cases. Arch Intern Med. 1997;155:2077-84.
4. Jernigan SM, Waldo FB. Racial incidence of hemolytic uremic syndrome. Pediatr Nephrol 1994;8:545-7.
5. United States Department of Agriculture. Economics of foodborne disease: E, coli. Available at: www.ers.usda.gov/briefing/ FoodborneDisease/ecoli/index.htm Accessed May 17, 2004.
6. Sears, CL. Update on shiga toxin-producing E. coli infections. Adv Stud Med 2003;3(5):259-64.
7. Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol 1998;9:1126- 33.
8. Tarr PI, Fouser LS, Stapleton AE, and others. Hemolytic- uremic syndrome in a six-year old girl after a urinary tract infection with shiga-toxin-producing Escherichia coli 0103:H2. N Engl J Med. 1996;335(9):635-8.
9. Robitaille P, Gonthier M, Grignon A, and others. Pancreatic injury in the hemolytic-uremic syndrome. Pediatr Nephrol 1997;11(5):631-2.
10. Thayu M, Chandler WL, Jelacic S, and others. Cardiac ischemia during hemolytic uremic syndrome. Pediatr Nephrol 2003;18(3):286-9.
11. Butani L, Polinsky MS, Kaiser BA, and others. Pleural effusion complicating acute peritoneal dialysis in hemolytic uremic syndrome. Pediatr Nephrol 1998;12(9):772-4.
12. Eisenhauer PB, Chaturvedi P, Fine RE, and others. Tumor necrosis factor alpha increases human cerebral endothelial cell Gb^sub 3^ and sensitivity to shiga toxin. Infect Immun 2001;69(3):1889-94.
13. Griffin PM, Tauxe RV: The epidemiology of infections caused by Escherichia coli 0157:H7, other enterohemorrhagic E. coli, and the associated hemolytic uremic syndrome. Epid Reviews 1991;13:60- 98.
14. Banatvala N, Griffin PM, Greene KD, and others. The United States national prospective hemolytic uremic syndrome study: microbiologic, serologic, clinical, and epidemiologic findings. J Infect Dis 2001;183(7):1063-70.
15. Pruimboom-Brees IM, Morgan TW, Ackermann MR, and others. Cattle lack vascular receptors for Escherichia colt 0157:H7 shiga toxins. Proc Natl Acad Sci USA 2000;97(19):10325-9.
16. Hoey DE, Currie C, Else RW, and others. Expression of receptors for verotoxin 1 from Escherichia coli 0157:H7 on bovine intestinal epithelium. J Med Microbiol 2002;51(2):143-9.
17. Griffin PM. Epidemiology of shiga toxin-producing Escherichia coli infections in humans in the United States. In: Kaper JB, and O’Brien AD, editors. Escherichia coli 0157:H7 and other shiga toxin- producing E. coli strains. Washington, DC: ASM Press 1998; 15-22.
18. Beutin L, Geier D, Steinruck H, and others. Prevalence and some properties of verotoxin (shiga-like toxin)-producing Escherichia coli in seven different species of healthy domestic animals. J Clin Microbiol 1993;31(9):2483-8.
19. Keene WE, Sazie E, Kok J, and others. An outbreak of Escherichia coli Ol 57:H7 infections traced to jerky made from deer meat. JAMA 1997;277(15):1229-31.
20. Varma JK, Greene KD, Reller ME, and others. An outbreak of E. coli 0157 infection following exposure to a contaminated building. JAMA 2003;290(20):2709-12.
21. Karmali MA, Arbus GS, Ish-Shalom N, and others. A family outbreak of hemolytic-uremic syndrome associated with verotoxin- producing Escherichia coti 0157:H7. Pediatr Nephrol 1988;2:409-14.
22. Belongia EA, Osterholm MT, Soler JT, and others. Transmission of Escherichia coli 0157:H7 infection in Minnesota child day-care facilities. JAMA 1993;269:883-8.
23. U.S. Food and Drug Administration. Testing for rapid detection of adulteration of food. Available at: www.fda.gov/oc/ bioterrorism/ report_congress.html Accessed May 17, 2004.
24. Meng J, Doyle MR Microbiology of shiga toxin-producing Escherichia coli in foods. In: Kaper JB, O’Brien AD, editors. Escherichia coli 0157:H7 and other shiga toxin-producing E. coli strains. Washington DC: ASM Press 1998;92-108.
25. Ismaili A, Philpott DJ, McKay DM, and others. Epithelial cell responses to shiga toxin-producing Escherichia coli infection. In: Kaper JB, O’Brien AD, editors. Escherichia coli 0157:H7 and other shiga toxin-producing E. coli strains. Washington, DC: ASM Press, 1998;213-25.
26. Alevriadou BR, Moake JL, and Turner NA. Real-time analysis of shear-dependent thrombus formation and its blockade by inhibitors of von Willebrand factor binding to platelets. Blood 1993;81(5):1263- 76.
27. Karpman D, Papadopoulou D, Nilsson K, and others. Platelet activation by shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic urmie syndrome. Blood 2001; 97(10):3100- 8.
28. Te Loo DMWM, van Hinsbergh VWM, van den Heuvel LPWJ, and others. Detection of verocytotoxin bound to circulating polymorphonuclear leukocytes of patients with hemolytic uremic syndrome. J Am Soc Nephrol 2001;12(4):800-6.
29. van Setten PA, Monnens LA, Verstraten RG, and others. Effects of verocytotoxin-1 on nonadherent human monocytes: binding characteristics, protein synthesis, and induction of cytokine release. Blood 1996;88:174-83.
30. Liu J, Akahoshi T, Sasahana T, and others. Inhibition of neutrophil apoptosis by verotoxin 2 derived from Escherichia coli 0157:H7. Infect Immun 1999;67(11):6203-5.
31. Lingwood CA. Verotoxin-binding in human renal sections. Nephron 1994;66(1):21-8.
32. Siegler RL. The hemolytic uremic syndrome. Pediatr Clin North Am 1995;42(6)1505-29.
33. Hutchison JS, Stanimirovic D, Shapiro A, and others. Shiga toxin (verotoxin) toxicity in human cerebral endothelial cells. In: Kaper JB, O’Brien AD, editors. Escherichia coli 0157:H7 and other shiga toxin-producing E. coli strains. Washington DC: ASM Press, 1998; 323-8.
34. Buckalew VM. Pathophysiology of progressive renal failure. South Med 1994;87:1028-33.
35. Huseman D, Gellermann J, Vollmer I, and others. Long-term prognosis of hemolytic uremic syndrome and effective renal plasma flow. Pediatr Nephrol 1999;13:672-7.
36. Brady HR, Clarkson MR. Acute Renal Failure. In: Schena FP, editor-in-chief. Nephrology. Maidenhead, Berkshire England: McGraw- Hill 2001:409-19.
37. Moake JL, Thrombotic microangiopathies. N Engl J Med 2002 347(8):589-600.
38. Bandarenko N, Brecher ME. United States Thrombotic Thrombocytopenic Purpura Apheresis Study Grotip (USTTPASG). Multicenter survey and retrospective analysis of current efficacy of therapeutic plasma exchange. J Clin Apheresis. 1998;13:133-41.
39. Hosier GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. Arch Pathol Lab Med 2003;127(7):834-9.
40. Moake JK, Turner NA, Stathopoulos NA, and others. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress- induced platelet aggregation. J Clin Invest 1986;78:1456-61.
41. Gerber A, \Karch H, Allerberger F, and others. Clinical course and the role of shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997-2000, in Germany and Austria: a prospective study. J Infect Dis 2002;186(4):493-500.
42. Pisoni R, Ruggenenti P, Remuzz G. Thrombotic microangiopathies including hemolytic-uremic syndrome. In: Johnson RJ, Feehally J, editors. Comprehensive Clinical Nephrology, 2nd ed. Philadelphia PA: 2003:413-23.
43. Gerritsen H, Turecek P, Schwarz HP, and others. Assay of von Willebrand factor (vWF)-cleaving protease based on decreased collagen binding affinity of degraded vWF. A tool for the diagnosis of thrombotic thrombocytopenic purpura (TTP). Thromb Haemost 1999;82:1386-9.
44. Chandler WL, Jelacic S, Boster DR. Prothrombotic coagulation abnormalities preceding the hemolytic-uremic syndrome. N Engl J Med 2002;346(1):23-32.
45. Cohen JA, Brecher ME, Bandarenko N. Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura. J Clin Apheresis 1998;13:16-9.
46. Corrigan JJ Jr, Boineau FG. Hemolytic-uremic syndrome. Pediatr Rev 2001;22(11):365-9.
47. Garg AX, Suri RS, Barrowman N, and others. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA 2003;290(10):1360-70.
48. Rust RS. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Available at: www.emedicine.com/neuro/ topic499.htm Accessed May 2, 2004.
49. Safdar N, Said A, Gangnon RE, and others. Risk of hemolytic uremic syndrome after antibiotic treatment of Escherichia coli 0157: H7 enteritis: a meta-analysis. JAMA 2002;288:996-1001.
50. Cimolai N, Carter JE, Morrison BJ. Risk factors for the progression of Escherichia coli 0157:H7 enteritis to hemolytic- uremic syndrome. J Pediatr 1990;116:589-92.
51. Krmar RT, Ferraris JR, Ramirez JA, and others. Ambulatory blood pressure monitoring after recovery from hemolytic uremic syndrome. Pediatr Nephrol 2001;16:812-6.
52. Remuzzi G. The future of reno-protection: frustrations and promises. Presented at: World Congress of Nephrology; June 8-12, 2003; Berlin, Germany.
53. Gagnadoux MF, Habib R, Gubler MC, and others. Long-term (15- 25 years) outcome of childhood hemolytic-uremic syndrome. Clin Nephrol 1996;46(1):39-41.
54. Fitzpatrick MM, Shah V, Trompeter RS, and others. Long term renal outcome of childhood haemolytic uraemic syndrome. BMJ 1991;303:489-92.
55. Nelid GH. Haemolytic-uraemic syndrome in practice. Lancet 1994;343(8894):398-401.
56. Fernandez GC, Rubel C, Dran G, and others. Shiga toxin-2 induces neutrophilia and neutrophil activation in a murine model of hemolytic urmie syndrome. Clin Immunol 2000;95(5):227-34.
57. Siegler RL. Spectrum of extrarenal involvement in postdiarrheal hemolytic-uremic syndrome. J Pediatr 1994;125:511-8.
58. Siegler RL. Postdiarrheal shiga toxin-mediated hemolytic uremic syndrome. JAMA 2003;290(10):1379-81.
59. Safe tables our priority. Why are people still dying from contaminated food? Available at: www.safetables.org/pdf/ STOP_Report.pdf. Accessed May 21, 2004.
60 Murano EA. Enhancing and evolving: advancements in 2003 and initiatives to improve food safety in 2004; February 12, 2004; San Antonio TX.
61. Bopp DJ, Sauders BD, Waring AL, and others. Detection, isolation, and molecular subryping of Escherichia coli 0157:H7 and Campylobacter jejuni associated with a large waterborne outbreak. J Clin Microbiol 2003;41(1):174-80.
62. Elliot EJ, Robins-Browne RM, O’Loughlin EV, and others. Nationwide study of haemolytic uraemic syndrome: clinical, microbiological, and epidemiological features. Arch Dis Child 2001;85:125-31.
63. Tarr PI, Neill MA. Perspective: the problem of non-0157:H7 : shiga toxin (verocytotoxin)-producing Escherichia coli. J Infect Dis 1996;174:1136-9.
64. Karch H, Janetzki-Mittmann C, Aleksic S, and others. Isolation of enterohemorrhagic Escherichia coli 0157 strains from patients with hemolytic-uremic syndrome by using immunomagnetic separation, DNA-based methods and direct culture. J Clin Microbiol 34:516-9.
65. United States General Accounting Office. Emerging infectious diseases: consensus on needed laboratory capacity could strengthen surveillance. Report to the Chairman, Subcommittee on Public Health, Committee on Health Education, Labor, and Pensions, U.S. Senate. Washington (DC): GAO/HEHS-99-26; 1999.
66. Ludwig K, Sarkim V, Bitzan M, and others. Shiga toxin- producing Escherichia coli infection and antibodies against Stx2 and Stx1 in household contacts of children with enteropathic hemolytic- uremic syndrome. J Clin Microbiol 2002;40(5):1773-82.
67. Byun Y, Ohmura M, Fujihashi K, and others. Nasal immunization with E. coli verotoxin 1 (VT)-B subunit and a nontoxic mutant of cholera toxin elicits serum neutralizing antibodies. Vaccine 2001;19:2061-70.
68. Suzaki Y, Ami Y, Nagata N, and others. Protection of monkeys against shiga toxin induced by shiga toxin-liposome conjugates. Int Arch Allergy Immunol 2002;127:294-8.
69. Mukherjee J, Chios K, Fishwild D, and others. Human Stx2- specific monoclonal antibodies prevent systemic complications of Escherichia coli 0157:H7 infection. Infect Immun 2002;70(2):612-9.
70. Haemolytic Uraemic Syndrome Help. H.U.S.H – A Poem. Available at: www.ecoli-tik.com/where.htm. Accessed April 22, 2004.
Heidi Andersen MT(ASCP) works at St John’s Hospital, Anderson IN and at Indiana University Hospital, Indianapolis IN.
Address for correspondence: Heidi Andersen MT(ASCP), 2007 B Parsons Drive, Indianapolis IN 46224. (317) 459-3023. firstname.lastname@example.org
This article was written while the author was a student in the Clinical Laboratory Science program at Indiana University, Indianapolis IN.
Copyright American Society for Clinical Laboratory Science Spring 2005