Hemolytic Uremic Syndrome (HUS): Pearls and Pitfalls

Authors: Drew Long, BS (@drewlong2232, Vanderbilt University School of Medicine, US Army) and Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) & Justin Bright, MD (@JBright2021)

A three-year-old male presents with mom for seven days of fever, diarrhea, and decreased activity. When you walk into the room, you note a listless-appearing boy with pallor. His eyes appear sunken. He is tachycardic, tachypneic, and febrile, but with normal blood pressure and saturations for age. He was born at term with no prior medical history, and his immunizations are up to date.

Mom states he has not been acting like himself with decreased eating, decreased urine output, and decreased activity. He has also been irritable and not engaged when playing.  No one else has been sick in the family, but the patient and his four-year-old brother did go to a birthday party at a petting zoo over a week ago.

You go through the pediatric assessment triangle (appearance, work of breathing, color/circulation). Your differential at this point is quite large, and with your concern for sepsis and hypovolemia, you provide a 20cc/kg bolus of NS. You obtain a CBC, renal function panel, lactate, urinalysis, and blood cultures and provide ceftriaxone. His labs return and you see the following:  WBC 18,000, hemoglobin/hematocrit 6.8/20.1, platelet count 18,000, creatinine 2.4, and BUN 63. When you return to the room, mom recalls that he had several days of bloody diarrhea, for which you obtain a stool specimen. This returns positive for blood.

Introduction

Diarrhea is a common presentation in pediatrics and emergency medicine.  When a child presents with diarrhea, it is often tempting to treat with antibiotics and fluids and subsequently discharge the patient, as complications from infectious etiologies of diarrhea are relatively rare.  One of the rare complications is Hemolytic Uremic Syndrome (HUS), which can lead to significant morbidity and even death.  HUS classically consists of the triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury (AKI).  It is a relatively rare disorder, with an estimated incidence in the United States and Western Europe of two to three per 100,000 children less than 5 years old.  HUS can be broken down into two classifications: 1) Diarrhea (typical) vs. no-diarrhea (atypical) and 2) primary vs. secondary.  Primary refers to defects in the complement activation system, while secondary includes infection (E. coli, S. pneumonia, and HIV), drug toxicity, autoimmune disorders, and several other etiologies.  Most cases of HUS in pediatric patients are secondary (non-complement mediated) and occur after a prodrome of diarrhea (typical).^1-3

HUS occurs most commonly during the summer in children under 3 years.^4,5  The most common cause of HUS in pediatric patients is Shiga-toxin producing Escherichia coli (STEC), which accounts for 90% of cases in pediatric patients.⁶  The most common serotype leading to HUS is Enterohemorrhagic E. coli (EHEC) O157:H7, which produces Shiga toxin 1 and 2.⁷  Interestingly, while exposure to STEC results in 38-61% of patients developing hemorrhagic colitis, only 6-9% of patients infected with STEC experience HUS.^8,9

STEC has a natural reservoir in cattle intestine, and has also been isolated from deer, sheep, goats, horses, dogs, and birds.¹ Human infection is due to ingestion of contaminated meat that is not properly cooked, unpasteurized dairy, and fruits or vegetables.  Fecal oral transmission may also occur, resulting in outbreaks in daycares or nursing homes.¹⁰

The second most common cause of HUS in children is infection with Streptococcus pneumoniae.  Pneumococcal-associated HUS occurs mainly in young infants and adults, accounting for 5-15% of childhood cases of HUS and 40% of non-STEC HUS.^11,12 Patients with pneumococcal associated HUS typically present with pneumonia (70%) or meningitis (20-30%) and is associated with a higher morbidity and mortality.^12-14

Primary HUS is more rare.  Inherited forms of HUS account for fewer than 3% of all cases (children and adults) of HUS.¹ The two main causes of the complement dysregulation seen in primary HUS are complement gene mutations and antibodies to complement factor H.¹⁵  This form is more common in adults and has a poorer prognosis.¹

As previously stated, the overwhelming majority of cases of HUS in children are due to STEC, and this will be the focus of the remainder of the discussion.

Pathogenesis

The main culprit in STEC HUS is the Shiga toxin.  The Shiga toxins are AB₅ toxins that halt protein synthesis within the host cell, leading to apoptosis.  HUS is thought to occur from damage to renal glomerular endothelial cells by Shiga toxin.  The pathogenesis of STEC begins with oral ingestion. STEC reaches the human gut and adheres to the epithelial cells of the GI mucosa.  Once it reaches systemic circulation, it is carried by polymorphonuclear cells to the kidneys. The toxin causes cell lysis, leading to detachment of the glomerular endothelial cells from the basement membrane while at the same time activating various cytokines, platelets, and the coagulation cascade.  As thrombi form in smaller vessels, red blood cells are damaged leading to microangiopathic hemolysis.  Unfortunately the toxin can deposit in any organ.  Renal insufficiency is thought to occur due to fibrin thrombi formation at three levels in the kidney: glomerular, arterial, and cortical. ^{1, 16-17}

Presentation

The classic course of HUS is a prodromal period of diarrhea followed by acute renal failure.  Diarrhea typically begins around 3 days following ingestion of STEC.¹  Patients with HUS will present with diarrhea in 91% of cases and with bloody diarrhea in 57% of cases.¹⁶  Patients usually have abdominal pain, vomiting, and non-bloody diarrhea, followed by bloody diarrhea approximately 5 days after first symptom onset.  Fever occurs in about 30% of cases, and neurologic symptoms are present in about 25% of cases.¹ Pain and vomiting/diarrhea can be severe and mimic conditions such as inflammatory bowel disease, appendicitis, and nephrolithiasis.^{1, 9}

The most common complication of HUS is acute kidney injury (AKI).   HUS is the one of the main causes of AKI in children under the age of three.⁷ Renal involvement varies from hematuria and proteinuria to severe renal failure and oliguria.  Acute renal failure with anuria occurs in 40% of cases, with 61% of those requiring dialysis.^1,18

In addition to the kidneys, HUS can affect many organ systems including the central nervous system, the gastrointestinal tract, the heart, the pancreas, and the liver.^19-21   Up to 25% of patients will display neurologic symptoms such as seizures and confusion, graying the line between HUS and thrombotic thrombocytopenic purpura (TTP).²² Hypertension has also been found to occur in 15% of patients.¹⁶  GI involvement from the perianal region to the esophagus can occur, including ischemia, colitis, necrosis, and perforation.

Differential Diagnosis

In a pediatric patient presenting with abdominal pain and diarrhea, HUS is not often considered at the top of the initial differential diagnosis.  The diagnosis can be further complicated as the patient may present without bloody diarrhea and may not even develop bloody diarrhea.  The main differential diagnoses to consider in the early stage, before the classic triad of anemia, thrombocytopenia, and acute kidney injury has developed, include other infectious causes of diarrhea.  These include Salmonella, Shigella, Campylobacter, Yersinia, Amebiasis, and Clostridium Difficile, all of which can cause abdominal pain, bloody diarrhea, leukocytosis, and fever.  The key differentiating factor is that infection with agents other than STEC should not develop anemia, thrombocytopenia, or acute renal failure.  Additionally other causes of severe abdominal pain and/or diarrhea/vomiting in the pediatric patient should be ruled out.  These conditions include appendicitis, intussusception, hernia, torsion (ovarian/testicular), obstruction, malrotation, inflammatory bowel disease, mesenteric adenitis, cholecystitis, pneumonia, strep pharyngitis, and nephrolithiasis.^7,16

Patients presenting in the later stages of HUS may have anemia, thrombocytopenia, and AKI in addition to the diarrhea prodrome.  The major conditions in the differential at this stage include diffuse intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), systemic vasculitis, and sepsis.  Laboratory abnormalities are often enough to differentiate DIC from HUS.  DIC is associated with thrombocytopenia as well as low levels of circulating fibrin, low levels of factors V and VIII, and prolongation of prothrombin (PT) and partial thromboplastin time (PTT).²³ Clinically, TTP can be difficult to differentiate from HUS.  TTP is due to a mutation in the von Willebrand factor-cleaving protease ADAMTS13.  TTP can present with fever, thrombocytopenia, and anemia.  However, neurologic symptoms are more prominent in TTP and acute kidney injury is less common.  Additionally, TTP is rare in children and much more common in adults.²⁴ Systemic vasculitis often presents with signs and symptoms not associated with HUS, such as a rash, arthralgia, and a normal platelet count.¹⁶  Sepsis can be confused for DIC due to multiorgan involvement in a sick patient.  While the history may be helpful in differentiating sepsis from HUS, sepsis is difficult to initially rule out.¹⁶ Table 1 summarizes the differential diagnosis of HUS based on the presenting signs and symptoms.

Table 1.  Differential Diagnosis of HUS^1,7,16

Lab abnormalities

Ordering the correct laboratory studies is essential in correctly diagnosing HUS and differentiating other conditions with similar presentations.  Any patient with a history of diarrhea, particularly if bloody, with multisystem involvement warrants a CBC with peripheral smear, renal function panel, urinalysis, liver function enzymes, and LDH.  Additionally, stool samples should be collected to test for occult blood.

After initial labs return, the triad of microangiopathic hemolytic anemia, renal failure, and thrombocytopenia must bring HUS to the top of the differential! The anemia seen in HUS is established by hemoglobin of less than 8 g/dL.  It is often more severe, with a range generally from 5.3 to 6.9 g/dL.  A Coombs test will be negative.  The anemia in HUS is microangiopathic, and a peripheral smear will reveal schistocytes (commonly around 10% of the smear) and burr/helmet cells.  These occur due to mechanical trauma of red blood cells in the vasculature.  Serum testing will demonstrate high LDH (most sensitive finding in ongoing hemolysis), high indirect bilirubin, and an increased reticulocyte count.  The platelet count most commonly is < 60,000/mm³ and is usually around 40,000/mm³.  Acute kidney injury can be difficult to initially diagnose in pediatric patients, as normal creatinine values vary based on age.  While the initial creatinine may or may not be helpful in determining AKI, subsequent measurements at 12 to 24 hours showing an increasing creatinine are often sufficient to confirm the diagnosis of AKI.  If a baseline creatinine is available, an increase in serum creatinine greater than 50% from baseline is often seen.  Additionally, electrolyte disturbances including hyperkalemia, hyperphosphatemia, and metabolic acidosis are common due to AKI.  Urine testing will often display hematuria and proteinuria. Fibrin degradation products will be elevated due to microthrombi formation.  Additionally, leukocytosis is common in typical HUS, with a worse prognosis occurring with increased white blood cell counts.  Laboratory findings associated with HUS are displayed in Table 2.^1,7,9,25,26

Table 2.  Lab results typically seen in HUS

As the most common cause of HUS is STEC, infection should be screened for in these patients.  This usually consists of testing for Shiga toxin in the stool, stool cultures, and testing for IgM and anti-lipopolysaccharide antibodies against the most frequent STEC serotypes.⁷ These labs will not change acute management of patients with HUS, but they will assist the inpatient team.

Treatment

As soon as HUS is suspected, consultation with the pediatric intensivist and nephrologist is warranted.   The mainstay of treatment is supportive with resuscitation and constant monitoring.   Major aspects of HUS that must be managed acutely include fluid status, anemia, thrombocytopenia, acute kidney injury, hypertension, and neurologic abnormalities.²⁷

• Fluid status must be carefully assessed in patients presenting with HUS, as they may present with large volume changes. Patients are often dehydrated due to diarrhea and/or vomiting and may require fluid resuscitation.  On the other hand, patients with oliguria or anuria may be fluid overloaded and require fluid restriction and/or dialysis.  In addition to fluid resuscitation and monitoring, electrolytes should be monitored and any abnormalities corrected.

• Patients presenting with hemoglobin of 6 g/dL or lower should receive product transfusion, which is required in about 80% of pediatric patients with STEC HUS.²⁸ A goal hemoglobin between 8-9 g/dL is recommended, as restoring hemoglobin to normal in these patients may lead to heart failure, pulmonary edema, and hypertension.²⁹ In order to avoid these complications, monitoring for signs of volume overload during transfusion is necessary, and transfusion should be halted if any signs of volume overload occur.

• Platelet transfusions are usually not implicated as platelets rarely fall below 10,000/mm³.  Platelet transfusion should be reserved for patients with active bleeding or patients with platelet counts below 30,000/mm³ who are undergoing an invasive procedure.²⁷

• In patients who develop renal insufficiency or renal failure, any nephrotoxic agents the patient is taking should be stopped. In addition, dialysis may be required, specifically if severe fluid overload, refractory electrolyte abnormalities, and symptomatic uremia occur.   However, early dialysis in patients with HUS has failed to show improved outcomes.²⁷

• Hypertension, if present, should be managed with calcium channel blockers such as nifedipine or nicardipine. Angiotensin converting enzyme inhibitors may result in decreased renal perfusion and are not recommended in patients presenting with HUS.^27,30

• The major neurologic abnormality that requires acute management is seizures. Seizures associated with HUS should receive immediate treatment with antiepileptics that can include a benzodiazepine and second line agents such as fosphenytoin and levetiracetam.²⁷

There is little evidence for the efficacy of other agents in the treatment of HUS, including heparin, prostacyclin, steroids, fibrinolytics, or immunoglobulins.^31,32  For patients presenting with suspected primary HUS (complement-mediated), plasma exchange may be beneficial.³³  Another treatment for both primary HUS and STEC HUS with CNS involvement  is eculizumab (monoclonal antibody to complement factor C5).²⁷  However, use of these agents should be left up to the pediatric intensivist or inpatient team.

Antibiotics?

Antibiotic use is controversial in HUS, and it is generally recommended that antibiotics be avoided unless sepsis is suspected. Several studies have shown an increased risk of HUS in STEC infections, thought to be due to release of Shiga toxin from the lysis of bacterial cells.^1,16  However, this line of reasoning must be weighed against the benefit of treatment of potential sepsis.

Summary

HUS consists of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.  HUS is a common cause of acute kidney injury in children, and the primary cause of HUS is STEC O157:H7. The clinical course includes vomiting, abdominal pain, fever and diarrhea which may become bloody several days later, followed by either resolution of these symptoms or systemic involvement resulting in the classical triad of HUS.  Any child presenting with a recent history of bloody diarrhea should be further evaluated with laboratories including a complete blood count with peripheral smear, renal function panel, urinalysis, liver functions tests, and LDH.  Treatment of HUS is supportive, with a focus on fluid and electrolyte management, correcting any laboratory abnormalities such as anemia or thrombocytopenia if warranted, and initiating dialysis if necessary for acute kidney injury.  In addition, the pediatric intensivist and nephrologist should be consulted as soon as possible for further management and guidance.

References/Further Reading

1. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol 2005; 16:1035.
2. Fitzpatrick M. Haemolytic uraemic syndrome and E coli O157. BMJ 1999; 318:684.
3. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 2005; 365:1073.
4. Pickering LK, Obrig TG, Stapleton FB. Hemolytic-uremic syndrome and enterohemorrhagic Escherichia coli.  Pediatr. Infect. Dis. J.  1994; 13:459-75; quiz 476.
5. Ostroff SM, Kobayashi JM, Lewis JH. Infections with Escherichia coli O157:H7 in Washington State.  The first year of statewide disease surveillance.  JAMA.  1989; 262:355-9.
6. Niaudet P. Overview of hemolytic uremic syndrome in children.  UpToDate.  September 2015.
7. Niaudet P. Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children.  UpToDate.  September 2015.
8. Vaillant V, Espié E, de Valk H, et al. Undercooked ground beef and person-to-person transmission as major risk factors for sporadic hemolytic uremic syndrome related to Shiga-toxin producing Escherichia coli infections in children in France. Pediatr Infect Dis J 2009; 28:650.
9. Constantinescu AR, et al. Non-enteropathic hemolytic uremic syndrome:  causes and short-term course.  Am J Kidney Dis. 2004;43(6):976.
10. Waters AM, et al. Hemolytic uremic syndrome associated with invasive pneumococcal disease:  the United Kingdom experience.  J Pediatr. 2007;151(2):140.
11. Banerjee R, et al. Streptococcus pneumoniae-associated hemolytic uremic syndrome among children in North America.  Pediatr Infect Dis J.  2011;30(9):736.
12. Spinale JM, Ruebner RL, Kaplan BS, Copelovitch L. Update on Streptococcus pneumoniae associated hemolytic uremic syndrome.  Curr Opin Pediatr.  2013 Apr;25(2):203-8.
13. Niaudet P. Complement-mediated hemolytic uremic syndrome.  UpToDate.  September 2015.
14. Amirlak I, and Amirlak B. Haemolytic uraemic syndrome:  An overview.  Nephrology 2006;11,213-218.
15. Melton-Celsa A, Mohawk K, Teel L, and O’Brien A. Pathogenesis of Shiga-Toxin Producing Escherichia coli.  Current Topics in Microbiology and Immunology (2012) 357: 67-103.
16. Habib R. Pathology of the hemolytic and uremic syndrome. In: Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura, Kaplan BS, Trompeter R, Moake J (Eds), Dekker, New York 1992. p.315.
17. de Buys Roessingh AS, de Lagausie P, Baudoin V, et al. Gastrointestinal complications of post-diarrheal hemolytic uremic syndrome. Eur J Pediatr Surg 2007; 17:328.
18. Thayu M, Chandler WL, Jelacic S, et al. Cardiac ischemia during hemolytic uremic syndrome. Pediatr Nephrol 2003; 18:286.
19. Andreoli S, Bergstein J. Exocrine and endocrine pancreatic insufficiency and calcinosis after hemolytic uremic syndrome. J Pediatr 1987; 110:816.
20. Nathanson S, Kwon T, Elmaleh M, et al. Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 2010; 5:1218.
21. Marder VJ, Martin SE, Francis CW, Colman RW. Consumptive thrombo-hemorrhagic disorders. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 2nd ed, Colman RW, Hirsh J, Marder VJ, Salzman EW (Eds), Lippincott, Philadelphia 1987. p.975.
22. Kessler C.S., Khan B.A., and Lai-Miller K.: Thrombotic thrombocytopenic purpura: a hematological emergency. J Emerg Med 2012; 43: pp. 538-544.
23. Prasad D. Acute kidney injury in children:  Clinical features, etiology, evaluation, and diagnosis.  UpToDate.  September 2015.
24. Siegler RL, Pavia AT, Christofferson RD, Milligan MK. A 20-year population-based study of postdiarrheal hemolytic uremic syndrome in Utah. Pediatrics 1994; 94:35.
25. Niaudet P. Treatment and prognosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children. UpToDate.  September 2015.
26. Brandt JR, Fouser LS, Watkins SL, et al. Escherichia coli O 157:H7-associated hemolytic-uremic syndrome after ingestion of contaminated hamburgers. J Pediatr 1994; 125:519.
27. Kaplan BS, Thomson PD, de Chadarévian JP. The hemolytic uremic syndrome. Pediatr Clin North Am 1976; 23:761.
28. Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 2005; 365:1073.
29. Robson WL, Fick GH, Jadavji T, Leung AK. The use of intravenous gammaglobulin in the treatment of typical hemolytic uremic syndrome.  Pediatr. Nephrol.  1991; 5:  289-92.
30. Perez N, Spizziri F, Rahman R, Suarez A, Larrubia C, Lasarte P. Steroids in the hemolytic uremic syndrome.  Pediatr. Nephrol.  1998; 12:  101-4.
31. Loirat C, Sonsino E, Hinglais N, et al. Treatment of the childhood haemolytic uraemic syndrome with plasma. A multicentre randomized controlled trial. The French Society of Paediatric Nephrology. Pediatr Nephrol 1988; 2:279.
32. http://www.ncbi.nlm.nih.gov/pubmed/25060255