Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 27, Number 7—July 2021
Research

Shiga Toxin–Associated Hemolytic Uremic Syndrome in Adults, France, 2009–2017

Benoît Travert1, Antoine Dossier1, Matthieu Jamme, Aurélie Cointe, Yahsou Delmas, Sandrine Malot, Alain Wynckel, Amélie Seguin, Claire Presne, Miguel Hie, Ygal Benhamou, David Ribes, Gabriel Choukroun, Steven Grangé, Alexandre Hertig, Emilie Cornec Le Gall, Lionel Galicier, Eric Daugas, Lila Bouadma, François-Xavier Weill, Elie Azoulay, Fadi Fakhouri, Agnès Veyradier, Stéphane Bonacorsi, Julien Hogan, Véronique Frémeaux-Bacchi, Eric Rondeau, Patricia Mariani-Kurkdjian, Paul CoppoComments to Author , and Centre de Référence des Microangiopathies Thrombotiques2
Author affiliations: Centre de Référence des Microangiopathies Thrombotiques, Paris, France (B. Travert, A. Dossier, M. Jamme, Y. Delmas, S. Malot, A. Wynckel, A. Seguin, C. Presne, M. Hie, Y. Benhamou, G. Choukroun, S. Grangé, A. Hertig, L. Galicier, E. Azoulay, F. Fakhouri, A. Veyradier, V. Frémeaux-Bacchi, E. Rondeau, P. Coppo); Université de Paris, Paris (B. Travert, A. Dossier, A. Cointe, L. Galicier, E. Daugas, L. Bouadma, E. Azoulay, A. Veyradier, S. Bonacorsi, J. Hogan, V. Frémeaux-Bacchi, P. Mariani-Kurkdjian); Hôpital Bichat—Claude Bernard, Paris (B. Travert, A. Dossier, E. Daugas, L. Bouadma); Sorbonne-Université, Paris (M. Jamme, M. Hie, A. Hertig, E. Rondeau, P. Coppo); Hôpital Tenon, Paris (M. Jamme, E. Rondeau); Hôpital Robert-Debré, Paris (A. Cointe, S. Bonacorsi, J. Hogan, P. Mariani-Kurkdjian); Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France (Y. Delmas); Hôpital Maison Blanche, Reims, France (A. Wynckel); Centre Hospitalier Universitaire de Caen, Caen, France (A. Seguin); Centre Hospitalier Universitaire d’Amiens, Amiens, France (C. Presne, G. Choukroun); Groupement Hospitalier Pitié-Salpêtrière, Paris (M. Hie, A. Hertig); Centre Hospitalier Universitaire de Rouen, Rouen, France (Y. Benhamou, S. Grangé); Centre Hospitalier Universitaire de Toulouse, Toulouse, France (D. Ribes); Centre Hospitalier Universitaire de Brest, Brest, France (E. Cornec-Le Gall); Hôpital Saint-Louis, Paris (L. Galicier, E. Azoulay); I; nstitut Pasteur, Paris (F.-X. Weill); Centre Hospitalier Universitaire de Nantes, Nantes, France (F. Fakhouri); Hôpital Lariboisière, Paris (A. Veyradier); Hôpital Européen Georges Pompidou, Paris (V. Frémeaux-Bacchi); Hôpital Saint Antoine, Paris (P. Coppo)

Main Article

Table 2

Clinical and biological characteristics of adults with Shiga toxin–associated hemolytic uremic syndrome, France, 2009–2017*

Characteristic Value
Clinical features
Fever 16/78 (20.5)
Diarrhea 80/96 (83.3)
Bloody diarrhea 47/96 (49.0)
Median time between symptom onset and hospitalization, d (IQR)†
 4 (1–9)
Renal manifestations
Median serum creatinine level, μmol/L (IQR)‡ 221.5 (145–391)
Acute kidney injury§ 96/96 (100.0)
KDIGO stage 1 3/96 (3.1)
KDIGO stage 2 17/96 (17.7)
KDIGO stage 3 74/96 (77.1)
Hemodialysis 61/96 (63.5)
Median time before dialysis, d¶ 3 (1–6)
Oligoanuria 47/96 (49.0)
Proteinuria (i.e., >0.5 g/L)
 33/42 (78.6)
Neurologic events
Any neurologic sign 73/96 (76.0)
Headache 18/96 (18.8)
Confusion 54/96 (56.3)
Seizure 30/96 (31.3)
Coma 36/96 (37.5)
Focal deficiency 25/96 (26.0)
Abnormal brain imaging# 23/58 (39.7)
Abnormal computed tomographic scan 5/38 (13.2)
Abnormal magnetic resonance imaging 20/42 (47.6)
Stroke, coma, or seizure
 50/96 (52.1)
Required mechanical ventilation
 34/96 (35.4)
Cardiac events
Any cardiac event 41/96 (42.7)
High troponin level 26/43 (60.5)
Acute coronary syndrome 4/96 (4.2)
New onset of heart arrhythmia 4/96 (4.2)
Acute heart failure 16/96 (16.7)
Recovered from cardiac arrest
 1/96 (1.0)
Laboratory features
Median leukocyte count, 109 cells/L (IQR) 10.5 (8.05–13.8)
Median platelet count, 109 cells/L (IQR)** 56 (36–120)
Platelet count <30, 109 cells/L** 19/96 (19.8)
Platelet count <30, 109 cells/L and serum creatinine <200 μmol/L** 5/96 (5.2)
Median hemoglobin, g/dL (IQR)** 10.4 (8.90–12.4)
Elevated lactate deshydrogenase (i.e., >250 IU/L) 78/79 (98.7)
C-reactive protein, mg/L (IQR)†† 48 (22–120)
Elevated lipase (i.e., >210 U/L) 5/32 (15.6)
Low CH50 (i.e., <70%) 26/67 (38.8)
Low C3 (i.e., <0.660 g/L) 5/69 (7.2)
Low C4 (i.e., <0.093 g/L) 3/69 (4.3)
Low complement factor H (i.e., <70%) 3/69 (4.3)
Low complement factor I (i.e., <70%) 1/69 (1.4)
Low CD46 (i.e., <13 µg/L) 23/35 (65.7)
Anti-FH antibody (>150 arbitrary units)‡‡
 2/69 (2.9)
Microbiological findings
Shiga toxin genotype 96/96 (100)
stx1+/stx2– 12/84 (14.3)
stx2+/stx1– 63/84 (75.0)
stx1+/stx2+ 9/84 (10.7)
Escherichia coli serogroup
O157 10/67 (14.9)
O104 8/67 (11.9)
O91 12/67 (17.9)
O80 4/67 (6.0)
O26 4/67 (6.0)
O103 3/67 (4.5)
O111 1/67 (1.5)
Minor serogroups§§ 25/67 (37.3)
Isolation site
Stool 90/96 (93.8)
Urine 7/96 (7.3)
Blood culture 4/96 (4.2)
Multisite¶¶ 5/96 (5.2)

*Values are no. with characteristic/total no. patients (%) except as indicated. KDIGO, Kidney Disease Improving Global Outcomes (15). †Time of symptom onset was the first reported day of diarrhea (for patients with diarrhea) or fever, confusion, abdominal pain, or nausea/vomiting (for patients without diarrhea). ‡Out of 90 patients; samples taken at admission. §Two patients had proteinuria (i.e., >1 g/L) but not elevation of serum creatinine. ¶Out of 60 patients requiring dialysis. #Recent brain lesions on magnetic resonance imaging, computed tomographic scan, or both. Fourteen patients had stroke lesions, 3 had posterior reversible encephalopathy syndrome lesions, 4 had intracerebral bleeds, and 12 had white matter lesions consistent with thrombotic microangiopathies. **Samples taken at admission. ††Out of 52 patients. ‡‡One patient had 242 arbitrary units and 1 had 800 arbitrary units. §§Four patients had strains belonging to O106, 3 to O128, 3 to O174, 2 to O113, 1 to O100, 1 to O126, 1 to O148, 1 to O177, 1 to O78, 1 to O84, and 7 to an O serogroup not typable at the time of identification. ¶¶Two patients had E. coli in urine and stool samples, 2 had E. coli in stool and blood samples, and 1 had E. coli in blood and urine samples.

Main Article

References
  1. Karmali  MA, Steele  BT, Petric  M, Lim  C. Sporadic cases of haemolytic-uraemic syndrome associated with faecal cytotoxin and cytotoxin-producing Escherichia coli in stools. Lancet. 1983;1:619–20. DOIPubMedGoogle Scholar
  2. Joseph  A, Cointe  A, Mariani Kurkdjian  P, Rafat  C, Hertig  A. Shiga toxin–associated hemolytic uremic syndrome: a narrative review. Toxins (Basel). 2020;12:67. DOIPubMedGoogle Scholar
  3. Fakhouri  F, Zuber  J, Frémeaux-Bacchi  V, Loirat  C. Haemolytic uraemic syndrome. Lancet. 2017;390:681–96. DOIPubMedGoogle Scholar
  4. Majowicz  SE, Scallan  E, Jones-Bitton  A, Sargeant  JM, Stapleton  J, Angulo  FJ, et al. Global incidence of human Shiga toxin-producing Escherichia coli infections and deaths: a systematic review and knowledge synthesis. Foodborne Pathog Dis. 2014;11:447–55. DOIPubMedGoogle Scholar
  5. Bruyand  M, Mariani-Kurkdjian  P, Le Hello  S, King  L-A, Van Cauteren  D, Lefevre  S, et al.; Réseau Français Hospitalier de Surveillance du Shu Pédiatrique. Paediatric haemolytic uraemic syndrome related to Shiga toxin-producing Escherichia coli, an overview of 10 years of surveillance in France, 2007 to 2016. Euro Surveill. 2019;24:24. DOIPubMedGoogle Scholar
  6. Gould  LH, Demma  L, Jones  TF, Hurd  S, Vugia  DJ, Smith  K, et al. Hemolytic uremic syndrome and death in persons with Escherichia coli O157:H7 infection, foodborne diseases active surveillance network sites, 2000-2006. Clin Infect Dis. 2009;49:1480–5. DOIPubMedGoogle Scholar
  7. Frank  C, Werber  D, Cramer  JP, Askar  M, Faber  M, an der Heiden  M, et al.; HUS Investigation Team. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N Engl J Med. 2011;365:1771–80. DOIPubMedGoogle Scholar
  8. Delmas  Y, Vendrely  B, Clouzeau  B, Bachir  H, Bui  H-N, Lacraz  A, et al. Outbreak of Escherichia coli O104:H4 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant. 2014;29:565–72. DOIPubMedGoogle Scholar
  9. Gould  LH, Jordan  JG, Dunn  J, Apostol  M, Griffin  PM; Emerging Infections Program FoodNet Working Group. Postdiarrheal hemolytic uremic syndrome in persons aged 65 and older in foodnet sites, 2000-2006. J Am Geriatr Soc. 2011;59:366–8. DOIPubMedGoogle Scholar
  10. Karpac  CA, Li  X, Terrell  DR, Kremer Hovinga  JA, Lämmle  B, Vesely  SK, et al. Sporadic bloody diarrhoea-associated thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome: an adult and paediatric comparison. Br J Haematol. 2008;141:696–707. DOIPubMedGoogle Scholar
  11. Soysal  N, Mariani-Kurkdjian  P, Smail  Y, Liguori  S, Gouali  M, Loukiadis  E, et al. Enterohemorrhagic Escherichia coli hybrid pathotype O80:H2 as a new therapeutic challenge. Emerg Infect Dis. 2016;22:1604–12. DOIPubMedGoogle Scholar
  12. Coimbra  RS, Grimont  F, Lenormand  P, Burguière  P, Beutin  L, Grimont  PA. Identification of Escherichia coli O-serogroups by restriction of the amplified O-antigen gene cluster (rfb-RFLP). Res Microbiol. 2000;151:639–54. DOIPubMedGoogle Scholar
  13. Coppo  P, Schwarzinger  M, Buffet  M, Wynckel  A, Clabault  K, Presne  C, et al.; French Reference Center for Thrombotic Microangiopathies. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLoS One. 2010;5:e10208. DOIPubMedGoogle Scholar
  14. Charlson  M, Szatrowski  TP, Peterson  J, Gold  J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47:1245–51. DOIPubMedGoogle Scholar
  15. International Society of Nephrology. KDIGO clinical practice guideline for acute kidney injury. 2012 [cited 2020 Jul 31]. https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf
  16. Frémeaux-Bacchi  V, Sellier-Leclerc  A-L, Vieira-Martins  P, Limou  S, Kwon  T, Lahoche  A, et al. Complement gene variants and Shiga toxin–producing Escherichia coli-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2019;14:364–77. DOIPubMedGoogle Scholar
  17. Ho  D, Imai  K, King  G, Stuart  EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw. 2011;42:1–28. DOIGoogle Scholar
  18. Karmali  MA, Karmali  MA. Emerging public health challenges of Shiga toxin–producing Escherichia coli related to changes in the pathogen, the population, and the environment. Clin Infect Dis. 2017;64:371–6. DOIPubMedGoogle Scholar
  19. Carter  AO, Borczyk  AA, Carlson  JAK, Harvey  B, Hockin  JC, Karmali  MA, et al. A severe outbreak of Escherichia coli O157:H7—associated hemorrhagic colitis in a nursing home. N Engl J Med. 1987;317:1496–500. DOIPubMedGoogle Scholar
  20. Ville  S, Ydee  A, Garandeau  C, Canet  E, Tissot  A, Cantarovich  D, et al. Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome in solid organ transplant recipients. Kidney Int. 2019;96:1423–4. DOIPubMedGoogle Scholar
  21. Farina  C, Gavazzeni  G, Caprioli  A, Remuzzi  G. Hemolytic uremic syndrome associated with verocytotoxin-producing Escherichia coli infection in acquired immunodeficiency syndrome. Blood. 1990;75:2465. DOIPubMedGoogle Scholar
  22. Vera-Aguilera  J, Duma  N, Gast  K, Alkhateeb  H, Tande  A, Leung  N, et al. Hemolytic uremic syndrome associated with Escherichia coli O157 infection in an allogenic stem cell transplant recipient. Mayo Clin Proc Innov Qual Outcomes. 2018;2:387–91. DOIPubMedGoogle Scholar
  23. Manière  L, Domenger  C, Camara  B, Giovannini  D, Malvezzi  P, Rostaing  L. An atypical case of Shiga toxin producing–Escherichia coli hemolytic and uremic syndrome (STEC-HUS) in a lung transplant recipient. Case Rep Transplant. 2019;2019:9465040. DOIPubMedGoogle Scholar
  24. Karmali  MA, Mascarenhas  M, Petric  M, Dutil  L, Rahn  K, Ludwig  K, et al. Age-specific frequencies of antibodies to Escherichia coli verocytotoxins (Shiga toxins) 1 and 2 among urban and rural populations in southern Ontario. J Infect Dis. 2003;188:1724–9. DOIPubMedGoogle Scholar
  25. Ergonul  Z, Clayton  F, Fogo  AB, Kohan  DE. Shigatoxin-1 binding and receptor expression in human kidneys do not change with age. Pediatr Nephrol. 2003;18:246–53. DOIPubMedGoogle Scholar
  26. Brando  RJF, Miliwebsky  E, Bentancor  L, Deza  N, Baschkier  A, Ramos  MV, et al. Renal damage and death in weaned mice after oral infection with Shiga toxin 2-producing Escherichia coli strains. Clin Exp Immunol. 2008;153:297–306. DOIPubMedGoogle Scholar
  27. Karpman  D, Connell  H, Svensson  M, Scheutz  F, Alm  P, Svanborg  C. The role of lipopolysaccharide and Shiga-like toxin in a mouse model of Escherichia coli O157:H7 infection. J Infect Dis. 1997;175:611–20. DOIPubMedGoogle Scholar
  28. Brandal  LT, Wester  AL, Lange  H, Løbersli  I, Lindstedt  B-A, Vold  L, et al. Shiga toxin-producing escherichia coli infections in Norway, 1992-2012: characterization of isolates and identification of risk factors for haemolytic uremic syndrome. BMC Infect Dis. 2015;15:324. DOIPubMedGoogle Scholar
  29. Käppeli  U, Hächler  H, Giezendanner  N, Beutin  L, Stephan  R. Human infections with non-O157 Shiga toxin-producing Escherichia coli, Switzerland, 2000-2009. Emerg Infect Dis. 2011;17:180–5. DOIPubMedGoogle Scholar
  30. Werber  D, Beutin  L, Pichner  R, Stark  K, Fruth  A. Shiga toxin-producing Escherichia coli serogroups in food and patients, Germany. Emerg Infect Dis. 2008;14:1803–6. DOIPubMedGoogle Scholar
  31. Adams  NL, Byrne  L, Smith  GA, Elson  R, Harris  JP, Salmon  R, et al. Shiga toxin–producing Escherichia coli O157, England and Wales, 1983–2012. Emerg Infect Dis. 2016;22:590–7. DOIPubMedGoogle Scholar
  32. Bielaszewska  M, Prager  R, Köck  R, Mellmann  A, Zhang  W, Tschäpe  H, et al. Shiga toxin gene loss and transfer in vitro and in vivo during enterohemorrhagic Escherichia coli O26 infection in humans. Appl Environ Microbiol. 2007;73:3144–50. DOIPubMedGoogle Scholar
  33. Byrne  L, Adams  N, Jenkins  C. Association between Shiga toxin–producing Escherichia coli O157:H7 stx gene subtype and disease severity, England, 2009–2019. Emerg Infect Dis. 2020;26:2394–400. DOIPubMedGoogle Scholar
  34. Lavrek  D, Lava  SAG, Milani  GP, Simonetti  GD, Bianchetti  MG, Giannini  O. Hemolytic-uremic syndrome after Escherichia coli urinary tract infection in humans: systematic review of the literature. J Nephrol. 2018;31:919–24. DOIPubMedGoogle Scholar
  35. Michael  M, Elliott  EJ, Ridley  GF, Hodson  EM, Craig  JC. Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Cochrane Database Syst Rev. 2009;1:CD003595. DOIPubMedGoogle Scholar
  36. Grisaru  S, Xie  J, Samuel  S, Hartling  L, Tarr  PI, Schnadower  D, et al.; Alberta Provincial Pediatric Enteric Infection Team. Associations between hydration status, intravenous fluid administration, and outcomes of patients infected with Shiga toxin–producing Escherichia coli: a systematic review and meta-analysis. JAMA Pediatr. 2017;171:68–76. DOIPubMedGoogle Scholar
  37. Keenswijk  W, Raes  A, De Clerck  M, Vande Walle  J. Is plasma exchange efficacious in Shiga toxin–associated hemolytic uremic syndrome? A narrative review of current evidence. Ther Apher Dial. 2019;23:118–25. DOIPubMedGoogle Scholar
  38. Kielstein  JT, Beutel  G, Fleig  S, Steinhoff  J, Meyer  TN, Hafer  C, et al.; Collaborators of the DGfN STEC-HUS registry. 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;27:3807–15. DOIPubMedGoogle Scholar
  39. Padmanabhan  A, Connelly-Smith  L, Aqui  N, Balogun  RA, Klingel  R, Meyer  E, et al. Guidelines on the use of therapeutic apheresis in clinical practice—evidence-based approach from the Writing Committee of the American Society for Apheresis: the eighth special issue. J Clin Apher. 2019;34:171–354. DOIPubMedGoogle Scholar
  40. Joseph  A, Rafat  C, Zafrani  L, Mariani-Kurkdjian  P, Veyradier  A, Hertig  A, et al. Early differentiation of Shiga toxin–associated hemolytic uremic syndrome in critically ill adults with thrombotic microangiopathy syndromes. Crit Care Med. 2018;46:e904–11. DOIPubMedGoogle Scholar
  41. Lapeyraque  A-L, 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;364:2561–3. DOIPubMedGoogle Scholar
  42. Wong  CS, Mooney  JC, Brandt  JR, Staples  AO, Jelacic  S, Boster  DR, et al. Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis. Clin Infect Dis. 2012;55:33–41. DOIPubMedGoogle Scholar
  43. Nitschke  M, Sayk  F, Härtel  C, Roseland  RT, Hauswaldt  S, Steinhoff  J, et al. Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. JAMA. 2012;307:1046–52. DOIPubMedGoogle Scholar

Main Article

1These first authors contributed equally to this article.

2Members of this group are listed at the end of this article.

Page created: May 20, 2021
Page updated: June 16, 2021
Page reviewed: June 16, 2021
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external