Skip to main content
Log in

A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript



Thrombotic microangiopathy (TMA) is a clinical syndrome encompassing a large group of rare but severe disorders including thrombotic thrombocytopenic purpura (TTP) and both typical and atypical forms of hemolytic uremic syndrome (HUS). The key role of the complement system is well known in TTP and atypical HUS, but recent reports describe its involvement in the pathogenesis of HUS secondary to gastrointestinal infections due to Shiga toxin-producing Escherichia coli (STEC).


TMA mainly affects the kidney, but extra-renal complications are frequently described. The involvement of the central nervous system (CNS) represents often a life-threatening condition and it can result in serious long-term disability in HUS patients who overcome the acute phase of illness. In the present study, we retrospectively analyzed a pediatric cohort of a single tertiary pediatric hospital in Southern Italy, in which this complication occurred in 12/54 children (22% of cases), of whom five with severe neurological involvement had been successfully treated with eculizumab.


The great clinical variability of brain injury in our cohort has led us to retrospectively build a “neurological score” useful to assess the clinical severity of neurologic involvement. Subjects with higher neurologic score due to the most severe CNS involvement resulted in the group of patients early treated with eculizumab, obtaining a good clinical response (four out five patients). In conclusion, the early treatment with eculizumab in children with severe neurological involvement during STEC-HUS was associated with complete regression of both acute kidney injury (AKI) and neurological lesions observed at magnetic resonance imaging (MRI).


A “neurological score” may be a useful tool to drive the early treatment of CNS complications in STEC-HUS with eculizumab, although future perspective controlled studies are urgently needed to validate this therapeutic approach.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others


  1. Copelovitch L, Kaplan BS (2008) The thrombotic microangiopathies. Pediatr Nephrol 23:1761–1767

    Article  Google Scholar 

  2. Kielstein JT, Beutel G, Fleig S, Steinhoff J, Meyer TN, Hafer C, Kuhlmann U, Bramstedt J, Panzer U, Vischedyk M, Busch V, Ries W, Mitzner S, Mees S, Stracke S, Nürnberger J, Gerke P, Wiesner M, Sucke B, Abu-Tair M, Kribben A, Klause N, Schindler R, Merkel F, Schnatter S, Dorresteijn EM, Samuelsson O, Brunkhorst R, Collaborators of the DGfN STEC-HUS registry (2012) 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 27:3807–1385

    Article  CAS  Google Scholar 

  3. Ardissino G, Tel F, Possenti I, Testa S, Consonni D, Paglialonga F, Salardi S, Borsa-Ghiringhelli N, Salice P, Tedeschi S, Castorina P, Colombo RM, Arghittu M, Daprai L, Monzani A, Tozzoli R, Brigotti M, Torresani E (2016) Early volume expansion and outcomes of hemolytic uremic syndrome. Pediatrics.

  4. Hickey CA, Beattie TJ, Cowieson J, Miyashita Y, Strife CF, Frem JC, Peterson JM, Butani L, Jones DP, Havens PL, Patel HP, Wong CS, Andreoli SP, Rothbaum RJ, Beck AM, Tarr PI (2011) Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome. Arch Pediatr Adolesc Med 165:884–889

    Article  Google Scholar 

  5. Johnson S, Taylor CM (2009) Hemolytic uremic syndrome, cap. 48. In: Pediatric nephrology, 6th edn. Springer Verlag, Berlin Heidelberg, pp 1155–1178

    Chapter  Google Scholar 

  6. Corogeanu D, Willmes R, Wolke M, Plum G, Utermöhlen O, Krönke M. (2012) Therapeutic concentrations of antibiotics inhibit Shiga toxin release from enterohemorrhagic E. coli O104:H4 from the 2011 German outbreak. BMC Microbiol 12:160

  7. Freedman SB, Xie J, Neufeld MS, Hamilton WL, Hartling L, Tarr P, Alberta Provincial Pediatric Enteric Infection Team (APPETITE), Nettel-Aguirre A, Chuck A, Lee B, Johnson D, Currie G, Talbot J, Jiang J, Dickinson J, Kellner J, MacDonald J, Svenson L, Chui L, Louie M, Lavoie M, Eltorki M, Vanderkooi O, Tellier R, Ali S, Drews S, Graham T, Pang XL, (Alberta Provincial Pediatric Enteric Infection Team,APPETITE) (2015) Shiga toxin-producing Escherichia coli infection, antibiotics, and risk of developing hemolytic uremic syndrome: a meta-analysis. Clin Infect Dis 62:1251–1258

    Article  Google Scholar 

  8. Angel Villegas N, Baronetti J, Albesa I, Etcheverría A, Becerra MC, Padola NL, Paraje MG (2015) Effect of antibioticsoncellular stress generated in Shigatoxin-producing Escherichia coli O157:H7 and non-O157 biofilms. Toxicol in Vitro 29:1692–1700

    Article  CAS  Google Scholar 

  9. Tajiri H, Nishi J, Ushijima K, Shimizu T, Ishige T, Shimizu M, Tanaka H, Brooks S (2015) A role for fosfomycin treatment in children for prevention of haemolytic-uraemic syndrome accompanying Shiga toxin-producing Escherichia coli infection. Int J Antimicrob Agents 46:586–589

    Article  CAS  Google Scholar 

  10. Rizzoni G, Claris-Appiani A, Edefonti A, Facchin P, Franchini F, Gusmano R, Imbasciati E, Pavanello L, Perfumo F, Remuzzi G (1998) Plasma infusion for hemolytic-uremic syndrome in children: results of a multicenter controlled trial. J Pediatr 112:284–290

    Article  Google Scholar 

  11. Slavicek J, Puretić Z, Novak M, Sarnavka V, Benjak V, Glavas-Boras S, Thune S (1995) The role of plasma exchange in the treatment of severe forms of hemolytic-uremic syndrome in childhood. Artif Organs 19:506–510

    Article  CAS  Google Scholar 

  12. Tummolo A, Colella V, Bellantuono R, Giordano M, Messina G, Puteo F, Sorino P, De Palo T (2012) [Apheresis in children: procedures and outcome.] G Ital. Nefrol Suppl 54:S125–S129

    Google Scholar 

  13. Colic E, Dieperink H, Titlestad K, Tepel M (2011) Management of an acute outbreak of diarrhoea-associated haemolyticuraemic syndrome with early plasma exchange in adults from southern Denmark: an observational study. Lancet 378:1089–1093

    Article  Google Scholar 

  14. Bitzan M, Schaefer F, Reymond D (2010) Treatment of typical (enteropathic) hemolytic uremic syndrome. Semin Thromb Hemost 36:594–610

    Article  CAS  Google Scholar 

  15. Michael M, Elliott EJ, Craig JC, Ridley G, Hodson EM (2009) Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis 53:259–272

    Article  Google Scholar 

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

    Article  Google Scholar 

  17. Matthies J, Hünseler C, Ehren R, Volland R, Körber F, Hoppe B, Weber LT, Habbig S (2016) Extrarenal manifestations in Shiga toxin-associated haemolytic uremic syndrome. Klin Paediatr 228:181–188

    Article  CAS  Google Scholar 

  18. Trachtman H, Austin C, Lewinski M, Stahl RA (2012) Renal and neurological involvement in typical Shiga toxin-associated HUS. Nat Rev Nephrol 8:658–669

    Article  CAS  Google Scholar 

  19. Hofer J, Rosales A, Fischer C, Giner T (2014) Extra-renal manifestations of complement-mediated thrombotic microangiopathies. Front Pediatr 97:1–16

    Google Scholar 

  20. Thurman JM, Marians R, Emlen W, Wood S, Smith C, Akana H, Holers VM, Lesser M, Kline M, Hoffman C, Christen E, Trachtman H (2009) Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 41920–1924

  21. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M, Proulx F, Clermont MJ, Le Deist F, Niaudet P (2011)Eculizumab in severe Shiga-toxin-associated HUS. N Engl J Med 364:2561–2563

  22. Germinario C, Caprioli A, Giordano M, Chironna M, Gallone MS, Tafuri S, Minelli F, Maugliani A, Michelacci V, Santangelo L, Mongelli O, Montagna C, Scavia G, all participants of the Outbreak investigation team (2016) Community-wide outbreak of haemolytic uraemic syndrome associated with Shiga toxin 2-producing Escherichia coli O26:H11 in southern Italy, summer 2013. Euro Surveill 21:30343

    Article  Google Scholar 

  23. Bielaszewska M, Mellmann A, Zhang W, Köck R, Fruth A, Bauwens A, Peters G, Karch H (2011) Characterisation of the Escherichia coli strain associated with an outbreak of haemolyticuraemic syndrome in Germany, 2011: a microbiological study. Lancet Infect Dis 11:671–676

    CAS  PubMed  Google Scholar 

  24. Nathanson S, Kwon T, Elmaleh M, Charbit M, Launay EA, Harambat J, Brun M, Ranchin B, Bandin F, Cloarec S, Bourdat-Michel G, Piètrement C, Champion G, Ulinski T, Deschênes G (2010) Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 5:1218–1228

    Article  CAS  Google Scholar 

  25. Gitiaux C, Krug P, Grevent D, Kossorotoff M, Poncet S, Eisermann M, Oualha M, Boddaert N, Salomon R, Desguerre I (2013) Brain magnetic resonance imaging pattern and outcome in children with haemolytic-uraemic syndrome and neurological impairment treated with eculizumab. Dev Med Child Neurol 55:758–765

    PubMed  Google Scholar 

  26. Ohlmann D, Hamann GF, Hassler M, Schimrigk K (1996) Involvement of the central nervous system in hemolytic uremic syndrome/thrombotic thrombocytopenic purpura. Nervenarzt 67:880–882

    Article  CAS  Google Scholar 

  27. Magnus T, Röther J, Simova O, Meier-Cillien M, Repenthin J, Möller F, Gbadamosi J, Panzer U, Wengenroth M, Hagel C, Kluge S, Stahl RK, Wegscheider K, Urban P, Eckert B, Glatzel M, Fiehler J, Gerloff C (2012) The neurological syndrome in adults during the 2011 northern German E. coli serotype O104:H4 outbreak. Brain 135:1850–1859

    Article  Google Scholar 

  28. Fujii J, Kinoshita Y, Kita T, Higure A, Takeda T, Tanaka N, Yoshida S (1996) Magnetic resonance imaging and histopathological study of brain lesions in rabbits given intravenous verotoxin 2. Infect Immun 64:5053–5060

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Shiraishi M, Ichiyama T, Matsushige T, Iwaki T, Iyoda K, Fukuda K, Makata H, Matsubara T, Furukawa S (2008) Soluble tumor necrosis factor receptor 1 and tissue inhibitor of metalloproteinase-1 in hemolytic uremic syndrome with encephalopathy. J Neuroimmunol 196:147–152

    Article  CAS  Google Scholar 

  30. Eisenhauer PB, Chaturvedi P, Fine RE, Ritchie AJ, Pober JS, Cleary TG, Newburg DS (2001) Tumor necrosis factor alpha increases human cerebral endothelial cell Gb3 and sensitivity to Shiga toxin. Infect Immun 69:1889–1894

    Article  CAS  Google Scholar 

  31. Ergonul Z, Clayton F, Fogo AB, Kohan DE (2003) Shigatoxin-1 binding and receptorexpression in human kidneys do not change with age. Pediatr Nephrol 18:246–253

    PubMed  Google Scholar 

  32. Grisaru S, Xie J, Samuel S, Hartling L, Tarr PI, Schnadower D, Freedman SB, Alberta Provincial Pediatric Enteric Infection Team (2017) 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 171:68–76

    Article  Google Scholar 

  33. Takahashi K, Funata N, Ikuta F, Sato S (2008) Neuronal apoptosis and inflammatory responses in the central nervous system of a rabbit treated with Shiga toxin-2. J Neuroinflammation 5:11

    Article  Google Scholar 

  34. Arieff AI, Llach F, Massry SG (1976) Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes Medicine 55:12112–12119

  35. Park SJ, Shin JI (2013) Inflammation and hyponatremia: an under recognized condition? Korean J Pediatr 56:519–522

    Article  CAS  Google Scholar 

  36. Teramoto T, Fukao T, Hirayama K, Asano T, Aoki Y, Kondo N (2009) Escherichia coli O-157-induced hemolytic uremic syndrome: usefulness of SCWP score for the prediction of neurological complication. Pediatr Int 51:107–109

    Article  CAS  Google Scholar 

  37. Tarr PI, Karpmann D (2012) Editorial commentary: Escherichia coli O104:H4 and hemolytic uremic syndrome: the analysis begins. Clinl Infect Dis 55:760–763

    Article  Google Scholar 

  38. Orth-Höller D, Würzner R (2014) Role of complement in enterohemorrhagic Escherichia coli-Induced hemolytic uremic syndrome (2014) Semin Thromb Hemost 40(4):503–507

  39. Hillmen P, Muus P, Röth A, Eletube MO, Risitano M, Schrezenmeier H, Szer J, Browne P, Maciejewski JP, Schubert J, Urbano-Ispizua A, de Castro C, Socié G, Brodsky RA (2013) Long term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 162:62–73

  40. Delmas Y, Vendrely B, Clouzeau B, Bachir H, Bui HN, Lacraz A, Hélou S, Bordes C, Reffet A, Llanas B, Skopinski S, Rolland P, Gruson D, Combe C (2014) Outbreak of Escherichia coli O104:H4 haemolyticuraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant 29:565–572

    Article  CAS  Google Scholar 

  41. Würzner R, Riedl M, Rosales A, Orth-Höller D (2014) Treatment of enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome (eHUS). Semin Thromb Hemost 40:508–516

    Article  Google Scholar 

  42. Loos S, Ahlenstiel T, Kranz B, Staude H, Pape L, Härtel C, Vester U, Buchtala L, Benz K, Hoppe B, Beringer O, Krause M, Müller D, Pohl M, Lemke J, Hillebrand G, Kreuzer M, König J, Wigger M, Konrad M, Haffner D, Oh J, Kemper MJ (2012) An outbreak of Shigatoxin producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children. Clin Infect Dis 55:753–759

    Article  CAS  Google Scholar 

  43. Luzzi I, García-Fernández A, Dionisi AM, Lucarelli C, Gattuso A, Gianfranceschi M, Maugliani A, Caprioli A, Morabito S, Scavia G (2017). Enter-Net Italia and the Italian registry of hemolytic uremic syndrome: surveillance of Salmonella, Campylobacter, Shiga-toxin producer Escherichia coli and Listeria monocytogenes infections (2010-2015). Reports of Italian Institute of Health (Rapporti ISTISAN) 17/34, ii, 70 p. (in Italian)

  44. Ardissino G, Daccò V, Testa S, Bonaudo R, Claris-Appiani A, Taioli E, Marra G, Edefonti A, Sereni F; ItalKid Project (2003) Epidemiology of chronic renal failure in children: data from the ItalKid project. Pediatrics 111(4 Pt 1):e382–e387

  45. Krug P., Oualha M., Boyer O. Gitiaux C., Grevent D., Boddaert N., Niaudet P., Salomon R. “Neurological involvement in E. coli-associated Hemolytic Uremic Syndrome”, 9th May 2012, Amsterdam,8th international symposium on Shiga toxin producing E. coli Infections

  46. Ward DM (2011) Conventional apheresis therapies: a review. J ClinApher 26:230–238

    Google Scholar 

  47. Greinacher A, Friesecke S, Abel P, Dressel A, Stracke S, Fiene M, Ernst F, Selleng K, Weissenborn K, Schmidt BM, Schiffer M, Felix SB, Lerch MM, Kielstein JT, Mayerle J (2011) Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4- associated haemolyticuraemic syndrome: a prospective trial. Lancet 378:1166–1173

    Article  Google Scholar 

  48. Flam B, Sackey P, Berge A, Zachau AC, Brink B, Lundberg S (2016) Diarrhea-associated hemolytic uremic syndrome with severe neurological manifestations treated with IgG depletion through immunoadsorption. J Nephrol 29:711–714

    Article  Google Scholar 

  49. Pape L, Hartmann H, Bange FC, Suerbaum S, Bueltmann E, Ahlenstiel-Grunow T (2015) Eculizumab in typical hemolytic uremic syndrome HUS) with neurological involvement. Medicine 94:e1000

  50. Saini A, Emke AR, Silva MC, Perlman SJ (2015) Response to eculizumab in Escherichia Coli O157: H7-induced hemolytic uremic syndrome with severe neurological manifestations. Clin Pediatr 54:387–389

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Mario Giordano.

Ethics declarations

Informed consent

We carried out a retrospective study based on registry data and no ethics approval was required. Nevertheless, all the children’s parents signed a written informed consent to collect their clinical data at time of hospital access.

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material


(DOCX 24 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Giordano, P., Netti, G.S., Santangelo, L. et al. A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement. Pediatr Nephrol 34, 517–527 (2019).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: