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Pediatric Nephrology

, Volume 34, Issue 3, pp 517–527 | Cite as

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

  • Paolo Giordano
  • Giuseppe Stefano Netti
  • Luisa Santangelo
  • Giuseppe Castellano
  • Vincenza Carbone
  • Diletta Domenica Torres
  • Marida Martino
  • Michela Sesta
  • Franca Di Cuonzo
  • Maria Chiara Resta
  • Alberto Gaeta
  • Leonardo Milella
  • Maria Chironna
  • Cinzia Germinario
  • Gaia Scavia
  • Loreto Gesualdo
  • Mario GiordanoEmail author
Original Article

Abstract

Background

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).

Methods

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.

Results

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).

Conclusions

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.

Keywords

Hemolytic uremic syndrome Neurological involvement Eculizumab Magnetic resonance imaging 

Notes

Compliance with ethical standards

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.

Supplementary material

467_2018_4112_MOESM1_ESM.docx (25 kb)
ESM 1 (DOCX 24 kb)

References

  1. 1.
    Copelovitch L, Kaplan BS (2008) The thrombotic microangiopathies. Pediatr Nephrol 23:1761–1767CrossRefGoogle Scholar
  2. 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 27:3807–1385CrossRefGoogle Scholar
  3. 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.  https://doi.org/10.1542/peds.2015-2153
  4. 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 165:884–889CrossRefGoogle Scholar
  5. 5.
    Johnson S, Taylor CM (2009) Hemolytic uremic syndrome, cap. 48. In: Pediatric nephrology, 6th edn. Springer Verlag, Berlin Heidelberg, pp 1155–1178CrossRefGoogle Scholar
  6. 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 12:160Google Scholar
  7. 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 62:1251–1258CrossRefGoogle Scholar
  8. 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 29:1692–1700CrossRefGoogle Scholar
  9. 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 46:586–589CrossRefGoogle Scholar
  10. 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 112:284–290CrossRefGoogle Scholar
  11. 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 19:506–510CrossRefGoogle Scholar
  12. 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–S129Google Scholar
  13. 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 378:1089–1093CrossRefGoogle Scholar
  14. 14.
    Bitzan M, Schaefer F, Reymond D (2010) Treatment of typical (enteropathic) hemolytic uremic syndrome. Semin Thromb Hemost 36:594–610CrossRefGoogle Scholar
  15. 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 53:259–272CrossRefGoogle Scholar
  16. 16.
    Scheiring J, Andreoli SP, Zimmerhackl LB (2008) Treatment and outcome of Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol 23:1749–1760CrossRefGoogle Scholar
  17. 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 228:181–188CrossRefGoogle Scholar
  18. 18.
    Trachtman H, Austin C, Lewinski M, Stahl RA (2012) Renal and neurological involvement in typical Shiga toxin-associated HUS. Nat Rev Nephrol 8:658–669CrossRefGoogle Scholar
  19. 19.
    Hofer J, Rosales A, Fischer C, Giner T (2014) Extra-renal manifestations of complement-mediated thrombotic microangiopathies. Front Pediatr 97:1–16Google Scholar
  20. 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. 41920–1924Google Scholar
  21. 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 364:2561–2563Google Scholar
  22. 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 21:30343CrossRefGoogle Scholar
  23. 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 11:671–676PubMedGoogle Scholar
  24. 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 5:1218–1228CrossRefGoogle Scholar
  25. 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 55:758–765PubMedGoogle Scholar
  26. 26.
    Ohlmann D, Hamann GF, Hassler M, Schimrigk K (1996) Involvement of the central nervous system in hemolytic uremic syndrome/thrombotic thrombocytopenic purpura. Nervenarzt 67:880–882CrossRefGoogle Scholar
  27. 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 135:1850–1859CrossRefGoogle Scholar
  28. 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 64:5053–5060PubMedPubMedCentralGoogle Scholar
  29. 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 196:147–152CrossRefGoogle Scholar
  30. 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 69:1889–1894CrossRefGoogle Scholar
  31. 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 18:246–253PubMedGoogle Scholar
  32. 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 171:68–76CrossRefGoogle Scholar
  33. 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 5:11CrossRefGoogle Scholar
  34. 34.
    Arieff AI, Llach F, Massry SG (1976) Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes Medicine 55:12112–12119Google Scholar
  35. 35.
    Park SJ, Shin JI (2013) Inflammation and hyponatremia: an under recognized condition? Korean J Pediatr 56:519–522CrossRefGoogle Scholar
  36. 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 51:107–109CrossRefGoogle Scholar
  37. 37.
    Tarr PI, Karpmann D (2012) Editorial commentary: Escherichia coli O104:H4 and hemolytic uremic syndrome: the analysis begins. Clinl Infect Dis 55:760–763CrossRefGoogle Scholar
  38. 38.
    Orth-Höller D, Würzner R (2014) Role of complement in enterohemorrhagic Escherichia coli-Induced hemolytic uremic syndrome (2014) Semin Thromb Hemost 40(4):503–507Google Scholar
  39. 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 162:62–73Google Scholar
  40. 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 29:565–572CrossRefGoogle Scholar
  41. 41.
    Würzner R, Riedl M, Rosales A, Orth-Höller D (2014) Treatment of enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome (eHUS). Semin Thromb Hemost 40:508–516CrossRefGoogle Scholar
  42. 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 55:753–759CrossRefGoogle Scholar
  43. 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)Google Scholar
  44. 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–e387Google Scholar
  45. 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 InfectionsGoogle Scholar
  46. 46.
    Ward DM (2011) Conventional apheresis therapies: a review. J ClinApher 26:230–238Google Scholar
  47. 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 378:1166–1173CrossRefGoogle Scholar
  48. 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 29:711–714CrossRefGoogle Scholar
  49. 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:e1000Google Scholar
  50. 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 54:387–389CrossRefGoogle Scholar

Copyright information

© IPNA 2018

Authors and Affiliations

  • Paolo Giordano
    • 1
  • Giuseppe Stefano Netti
    • 2
  • Luisa Santangelo
    • 1
  • Giuseppe Castellano
    • 3
  • Vincenza Carbone
    • 1
  • Diletta Domenica Torres
    • 1
  • Marida Martino
    • 1
  • Michela Sesta
    • 4
  • Franca Di Cuonzo
    • 5
  • Maria Chiara Resta
    • 5
  • Alberto Gaeta
    • 6
  • Leonardo Milella
    • 7
  • Maria Chironna
    • 8
  • Cinzia Germinario
    • 8
  • Gaia Scavia
    • 9
  • Loreto Gesualdo
    • 3
  • Mario Giordano
    • 1
    Email author
  1. 1.Pediatric Nephrology and Dialysis UnitPediatric Hospital “Giovanni XXIII”BariItaly
  2. 2.Clinical Pathology Unit and Center for Molecular Medicine, Department of Medical and Surgical SciencesUniversity of FoggiaFoggiaItaly
  3. 3.Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ TransplantationUniversity of Bari “Aldo Moro”BariItaly
  4. 4.Pediatric Neurology UnitPediatric Hospital “Giovanni XXIII”BariItaly
  5. 5.Department of NeuroradiologyUniversity of Bari “Aldo Moro”BariItaly
  6. 6.Pediatric Radiology UnitPediatric Hospital “Giovanni XXIII”BariItaly
  7. 7.Intensive Care UnitPediatric Hospital “Giovanni XXIII”BariItaly
  8. 8.Department of Biomedical Science and Human OncologyUniversity of Bari “Aldo Moro”BariItaly
  9. 9.Food Safety, Nutrition and Veterinary Public Health DepartmentNational Institute of HealthRomeItaly

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