Pediatric Hemolytic Uremic Syndrome Clinical Presentation

  • Author: Robert S Gillespie, MD, MPH; Chief Editor: Craig B Langman, MD  more...
 
Updated: Jun 13, 2016
 

History

Patients with Shiga toxin–producing E coli hemolytic-uremic syndrome (STEC-HUS) experience several days of diarrhea, with or without vomiting, followed by sudden onset of symptoms such as irritability and pallor. In more than 80% of patients, the diarrhea is visibly bloody. Other symptoms include restlessness, oliguria, edema, and macroscopic hematuria. In some patients, the prodrome may improve as hemolytic-uremic syndrome symptoms begin. The clinical picture may mimic that of an acute abdomen. In patients infected with a Shiga toxin (Stx)–producing strain of E coli, hemolytic-uremic syndrome occurs in 5-15%.

The risk of progression to hemolytic-uremic syndrome is increased in very young or elderly persons, in patients who have been treated with antimotility drugs or antibiotics, and in patients with a fever or a high leukocyte count.

The history should include inquiry about possible recent exposure to E coli, such as consuming undercooked meat, encounters with livestock or petting zoos, contacts with other persons with diarrhea, and attendance at daycare or school. However, most cases of STEC-HUS are sporadic, with no clearly identifiable source of infection, even when stool culture yields a toxigenic organism. Outbreaks involving multiple persons more commonly lead to a source.

Atypical hemolytic-uremic syndrome (aHUS) may follow a respiratory illness, especially when caused by S pneumoniae.

Features of all forms of hemolytic-uremic syndrome include the following:

  • Hematology: Hemolysis occurs in all patients with hemolytic-uremic syndrome. It can proceed rapidly, resulting in a rapid fall of the hematocrit. Platelet counts usually fall below 40,000/µL. However, the degree of thrombocytopenia does not correlate with the severity of hemolytic-uremic syndrome, and some children can maintain relatively normal kidney function despite severe hematologic abnormalities. Many patients have petechiae, purpura, and oozing from venipuncture sites. Overt bleeding is less common.
  • CNS: Patients often present with sudden onset of lethargy and irritability. Other findings may include ataxia, coma, seizures, cerebral swelling, hemiparesis, and other focal neurologic signs. CNS changes may be caused by cerebral ischemia from microthrombi, effects of hypertension, hyponatremia, or uremia. aHUS tends to be associated with a greater number of neurologic symptoms than STEC-HUS.
  • Renal system: Acute renal insufficiency usually begins with the onset of hemolysis. Although patients have decreased urine output, frequent diffuse watery stools may mask this sign. If renal insufficiency is not recognized and treated, hyponatremia, hyperkalemia, severe acidosis, ascites, edema, pulmonary edema, and hypertension ensue.
  • GI tract: STEC-HUS is usually preceded by 3-12 days of watery or bloody diarrhea. Vomiting and crampy abdominal pain are also common. Note that diarrhea may improve as the other hemolytic-uremic syndrome symptoms begin (eg, thrombocytopenia, renal insufficiency). Life-threatening complications include intestinal perforation or necrosis. Even without these complications, the colitis of hemolytic-uremic syndrome may cause severe abdominal pain, which may persist for several days into the illness.
  • Infectious signs: Fever is present in 5-20% of patients. The presence of fever, leukocytosis, or both is a prognostic indicator of the risk of developing more severe hemolytic-uremic syndrome.
  • Pancreas: Mild pancreatic involvement is common but can be severe on occasion, with necrosis, pseudocysts, or both, which can leave the patient with type 1 diabetes and, on rare occasion, exocrine dysfunction.
  • Cardiovascular: Congestive heart failure may occur.
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Physical

Blood pressure may be elevated unless the patient is volume depleted (eg, from diarrhea). The child appears ill and pale. Abdominal pain and tenderness may be present, possibly severe. Peripheral edema may be present. Petechiae, purpura, or oozing from venipuncture sites may be present.

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Causes

STEC-HUS

GI tract infection with Stx–producing E coli (STEC) precedes most cases of STEC-HUS. Stx1 is identical to the Stx produced by Shigella dysenteriae. Stx2 has a 55-60% amino acid homology with Stx. They injure the gut and lead to hemorrhagic colitis. Most cases worldwide are associated with STEC 0157:H7 infection. This organism is very resilient; viable bacteria have been reported in environments up to 10 months following initial contamination. Aside from Stx production, this bacteria produces virulence factors that mediate tight adherence to the host cell, facilitating transluminal transport of the toxins into the systemic circulation. Cattle are the major reservoir for human infection. The use of antimotility agents, antidiarrheal agents, and antibiotics has been reported to increase the risk of developing hemolytic-uremic syndrome. E coli O104:H4 was responsible for a large outbreak of hemolytic-uremic syndrome in Germany.

Other causes of hemolytic-uremic syndrome include infection by the following:

  • S dysenteriae (established as an etiologic agent)
  • Salmonella typhi (established as an etiologic agent)
  • Campylobacter jejuni (established as an etiologic agent)
  • Bacteroides species
  • Entamoeba histolytica
  • Aeromonas hydrophilia
  • Organisms of the class Microtatobiotes

aHUS

Causes of aHUS include the following:

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Contributor Information and Disclosures
Author

Robert S Gillespie, MD, MPH Physician, Department of Pediatrics, Cook Children's Medical Center

Disclosure: Received consulting fee from Alexion Pharmaceuticals for consulting.

Coauthor(s)

Ronald D Prauner, MD Assistant Professor of Pediatrics, F Edward Herbert School of Medicine, Uniformed Services of the Health Sciences; Assistant Deputy Commander for Medicine; Fort Belvoir Community Hospital, Fort Belvoir, VA; Consultant to the Army Surgeon General for Pediatric Subspecialties; Staff Pediatric Hematologist-Oncologist, Fort Belvoir Community Hospital

Ronald D Prauner, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Christian Medical and Dental Associations, Children's Oncology Group

Disclosure: Nothing to disclose.

Craig S Wong, MD, MPH Assistant Professor, Division of Pediatric Nephrology, Department of Pediatrics, University of New Mexico School of Medicine; Director of Pediatric Kidney Transplantation, Division of Pediatric Nephrology, Department of Pediatrics, University of New Mexico Transplant Services, Children's Hospital of New Mexico

Craig S Wong, MD, MPH is a member of the following medical societies: American Society of Nephrology, American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Luther Travis, MD Professor Emeritus, Departments of Pediatrics, Nephrology and Diabetes, University of Texas Medical Branch School of Medicine

Luther Travis, MD is a member of the following medical societies: Alpha Omega Alpha, American Federation for Medical Research, International Society of Nephrology, Texas Pediatric Society

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, The Ann and Robert H Lurie Children's Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, International Society of Nephrology

Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Raptor Pharmaceuticals; Eli Lilly and Company; Dicerna.

Additional Contributors

Richard Neiberger, MD, PhD Director of Pediatric Renal Stone Disease Clinic, Associate Professor, Department of Pediatrics, Division of Nephrology, University of Florida College of Medicine and Shands Hospital

Richard Neiberger, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Medical Research, American Medical Association, American Society of Nephrology, American Society of Pediatric Nephrology, Christian Medical and Dental Associations, Florida Medical Association, International Society for Peritoneal Dialysis, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Shock Society, Sigma Xi, Southern Medical Association, Southern Society for Pediatric Research, Southwest Pediatric Nephrology Study Group

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Tamara Biega, MD, to the original writing and development of this article.

References
  1. Uslu-Gökceoglu A, Dogan CS, Comak E, Koyun M, Akman S. Atypical Hemolytic Uremic Syndrome due to Factor H Autoantibody. Turk J Pediatr. 2013 Jan-Feb. 55(1):86-9. [Medline].

  2. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Jul 23. 361(4):345-57. [Medline].

  3. 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. [Medline].

  4. Loos S, Ahlenstiel T, Kranz B, Staude H, Pape L, Härtel C, et al. An outbreak of Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children. Clin Infect Dis. 2012 Sep. 55(6):753-9. [Medline].

  5. [Guideline] Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol. 2009 Apr. 24(4):687-96. [Medline].

  6. Gitiaux C, Krug P, Grevent D, Kossorotoff M, Poncet S, Eisermann M, et al. Brain magnetic resonance imaging pattern and outcome in children with haemolytic-uraemic syndrome and neurological impairment treated with eculizumab. Dev Med Child Neurol. 2013 May 10. [Medline].

  7. Ake JA, Jelacic S, Ciol MA, Watkins SL, Murray KF, Christie DL. Relative nephroprotection during Escherichia coli O157:H7 infections: association with intravenous volume expansion. Pediatrics. 2005 Jun. 115(6):e673-80. [Medline].

  8. Ardissino G, Tel F, Possenti I, Testa S, Consonni D, Paglialonga F, et al. Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome. Pediatrics. 2016 Jan. 137 (1):[Medline].

  9. Gillespie RS, Seidel K, Symons JM. Effect of fluid overload and dose of replacement fluid on survival in hemofiltration. Pediatr Nephrol. 2004 Dec. 19(12):1394-9. [Medline].

  10. Foland JA, Fortenberry JD, Warshaw BL, Pettignano R, Merritt RK, Heard ML. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med. 2004 Aug. 32(8):1771-6. [Medline].

  11. Maxvold NJ, Smoyer WE, Custer JR, Bunchman TE. Amino acid loss and nitrogen balance in critically ill children with acute renal failure: a prospective comparison between classic hemofiltration and hemofiltration with dialysis. Crit Care Med. 2000 Apr. 28(4):1161-5. [Medline].

  12. Murphy EJ. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care. 2005 Jun. 33(3):311-22. [Medline].

  13. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004 Nov. 28(5):497-504. [Medline].

  14. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, et al. Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med. 2011 Jun 30. 364(26):2561-3. [Medline].

  15. Kielstein JT, Beutel G, Fleig S, Steinhoff J, Meyer TN, Hafer C, et al. Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic-uraemic syndrome: an analysis of the German STEC-HUS registry. Nephrol Dial Transplant. 2012 Oct. 27(10):3807-15. [Medline].

  16. Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J, et al. Validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ. 2012 Jul 19. 345:e4565. [Medline]. [Full Text].

  17. Trachtman H, Austin C, Lewinski M, Stahl RA. Renal and neurological involvement in typical Shiga toxin-associated HUS. Nat Rev Nephrol. 2012 Nov. 8(11):658-69. [Medline].

  18. Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 2015 May. 87 (5):1061-73. [Medline].

  19. Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2016 Jan. 31 (1):15-39. [Medline].

  20. Michael M, Elliott EJ, Craig JC, Ridley G, Hodson EM. Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis. 2009 Feb. 53(2):259-72. [Medline].

  21. Nguyen L, Li X, Duvall D, Terrell DR, Vesely SK, George JN. Twice-daily plasma exchange for patients with refractory thrombotic thrombocytopenic purpura: the experience of the Oklahoma Registry, 1989 through 2006. Transfusion. 2008 Feb. 48(2):349-57. [Medline].

  22. von Baeyer H. Plasmapheresis in thrombotic microangiopathy-associated syndromes: review of outcome data derived from clinical trials and open studies. Ther Apher. 2002 Aug. 6(4):320-8. [Medline].

  23. Filler G, Radhakrishnan S, Strain L, Hill A, Knoll G, Goodship TH. Challenges in the management of infantile factor H associated hemolytic uremic syndrome. Pediatr Nephrol. 2004 Aug. 19(8):908-11. [Medline].

  24. Soliris (eculizumab) [package insert]. Cheshire, CT: Alexion Pharmaceutical. 2011. Available at [Full Text].

  25. Loirat C, Babu S, Furman R, Sheerin N, Cohen D, Gaber O, et al. Eculizumab Efficacy and Safety in Patients With Atypical Hemolytic Uremic Syndrome (aHUS) Resistant to Plasma Exchange/Infusion [poster]. Presented at the 16th Congress of European Hematology Association (EHA). 2011. London, UK.

  26. Loirat C, Muus P, Legendre C, Douglas K, Hourmant M, Delmas Y, et al. A Phase II Study of Eculizumab in Patients With Atypical Hemolytic Uremic Syndrome Receiving Chronic Plasma Exchange/Infusion [poster]. Presented at the 16th Congress of European Hematology Association (EHA). 2011. London, UK.

  27. Gulleroglu K, Fidan K, Hançer VS, Bayrakci U, Baskin E, Soylemezoglu O. Neurologic involvement in atypical hemolytic uremic syndrome and successful treatment with eculizumab. Pediatr Nephrol. 2013 May. 28(5):827-30. [Medline].

  28. Salvadori M, Bertoni E. Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations. World J Nephrol. 2013 Aug 6. 2(3):56-76. [Medline]. [Full Text].

  29. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012 Nov. 8(11):643-57. [Medline].

  30. Ardissino G, Testa S, Possenti I, Tel F, Paglialonga F, Salardi S, et al. Discontinuation of Eculizumab Maintenance Treatment for Atypical Hemolytic Uremic Syndrome: A Report of 10 Cases. Am J Kidney Dis. 2014 Mar 19. [Medline].

  31. Saland JM, Ruggenenti P, Remuzzi G. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2009 May. 20(5):940-9. [Medline].

  32. Saland JM, Shneider BL, Bromberg JS, et al. Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2009 Jan. 4(1):201-6. [Medline]. [Full Text].

  33. Jalanko H, Peltonen S, Koskinen A, et al. Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H. Am J Transplant. 2008 Jan. 8(1):216-21. [Medline].

  34. Saland JM, Emre SH, Shneider BL, et al. Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am J Transplant. 2006 Aug. 6(8):1948-52. [Medline].

  35. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, et al. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007 Aug. 18(8):2392-400. [Medline].

  36. Zimmerhackl LB, Besbas N, Jungraithmayr T, et al. Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost. 2006 Mar. 32(2):113-20. [Medline].

  37. Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol. 2011 Aug. 26(8):1325-9. [Medline].

  38. Krid S, Roumenina LT, Beury D, Charbit M, Boyer O, Frémeaux-Bacchi V, et al. Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. Am J Transplant. 2012 Jul. 12(7):1938-44. [Medline].

  39. Xie L, Nester CM, Reed AI, Zhang Y, Smith RJ, Thomas CP. Tailored eculizumab therapy in the management of complement factor H-mediated atypical hemolytic uremic syndrome in an adult kidney transplant recipient: a case report. Transplant Proc. 2012 Dec. 44(10):3037-40. [Medline].

  40. Palma LM, Langman CB. Critical appraisal of eculizumab for atypical hemolytic uremic syndrome. J Blood Med. 2016. 7:39-72. [Medline].

  41. Greenbaum LA, Fila M, Ardissino G, Al-Akash SI, Evans J, Henning P, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney Int. 2016 Mar. 89 (3):701-11. [Medline].

  42. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000 Jun 29. 342(26):1930-6. [Medline].

  43. Iijima K, Kamioka I, Nozu K. Management of diarrhea-associated hemolytic uremic syndrome in children. Clin Exp Nephrol. 2008 Feb. 12(1):16-9. [Medline].

  44. Garg AX, Salvadori M, Okell JM, et al. Albuminuria and estimated GFR 5 years after Escherichia coli O157 hemolytic uremic syndrome: an update. Am J Kidney Dis. 2008 Mar. 51(3):435-44. [Medline].

  45. Harrison P. Early Eculizumab Treatment Improves Outcomes in Atypical HUS. Medscape Medical News. Available at http://www.medscape.com/viewarticle/846279. June 11, 2015; Accessed: September 29, 2015.

  46. Bauer A, Loos S, Wehrmann C, Horstmann D, Donnerstag F, Lemke J, et al. Neurological involvement in children with E. coli O104:H4-induced hemolytic uremic syndrome. Pediatr Nephrol. 2014 Sep. 29(9):1607-15. [Medline].

  47. Nathan DG, Orkin SH, eds. Nathan and Oski's Hematology of Infancy and Childhood. 5th ed. Harcourt Health Sciences; 1998. Vol 1: 531-6.

  48. Rangel JM, Sparling PH, Crowe C, et al. Epidemiology of Escherichia coli O157:H7 outbreaks, United States, 1982-2002. Emerg Infect Dis. 2005 Apr. 11(4):603-9. [Medline].

  49. Siegler R, Oakes R. Hemolytic uremic syndrome; pathogenesis, treatment, and outcome. Curr Opin Pediatr. 2005 Apr. 17(2):200-4. [Medline].

 
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Peripheral blood smear in hemolytic-uremic syndrome (HUS) showing many schistocytes and RBC fragments due to hemolysis, and relatively few platelets reflective of thrombocytopenia.
Micrograph of a glomerulus in hemolytic-uremic syndrome, showing thrombi and red blood cell fragments in the capillary space. Courtesy of Xin J (Joseph) Zhou, MD, Renal Path Diagnostics, Pathologists BioMedical Labs.
 
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