Top

Published in:

01-08-2018 | Original Article

Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study

Authors: Lucas Percheron, Raluca Gramada, Stéphanie Tellier, Remi Salomon, Jérôme Harambat, Brigitte Llanas, Marc Fila, Emma Allain-Launay, Anne-Laure Lapeyraque, Valerie Leroy, Anne-Laure Adra, Etienne Bérard, Guylhène Bourdat-Michel, Hassid Chehade, Philippe Eckart, Elodie Merieau, Christine Piètrement, Anne-Laure Sellier-Leclerc, Véronique Frémeaux-Bacchi, Chloe Dimeglio, Arnaud Garnier

Published in: Pediatric Nephrology | Issue 8/2018

Abstract

Background

Hemolytic uremic syndrome related to Shiga-toxin-secreting Escherichia coli infection (STEC-HUS) remains a common cause of acute kidney injury in young children. No specific treatment has been validated for this severe disease. Recently, experimental studies highlight the potential role of complement in STEC-HUS pathophysiology. Eculizumab (EC), a monoclonal antibody against terminal complement complex, has been used in severe STEC-HUS patients, mostly during the 2011 German outbreak, with conflicting results.

Methods

On behalf of the French Society of Pediatric Nephrology, we retrospectively studied 33 children from 15 centers treated with EC for severe STEC-HUS. Indication for EC was neurologic involvement in 20 patients, cardiac and neurologic involvement in 8, cardiac involvement in 2, and digestive involvement in 3. Based on medical status at last follow-up, patients were divided into two groups: favorable (n = 15) and unfavorable outcomes (n = 18).

Results

Among patients with favorable outcome, 11/14 patients (79%) displayed persistent blockade of complement activity before each EC reinjection. Conversely, in patients with unfavorable outcome, only 9/15 (53%) had persistent blockade (p = n.s.). Among 28 patients presenting neurological symptoms, 19 had favorable neurological outcome including 17 with prompt recovery following first EC injection. Only two adverse effects potentially related to EC treatment were reported.

Conclusions

Taken together, these results may support EC use in severe STEC-HUS patients, especially those presenting severe neurological symptoms. The study, however, is limited by absence of a control group and use of multiple therapeutic interventions in treatment groups. Thus, prospective, controlled trials should be undertaken.

Rosales A, Hofer J, Zimmerhackl L-B, Jungraithmayr TC, Riedl M, Giner T, Strasak A, Orth-Höller D, Würzner R, Karch H (2012) Need for long-term follow-up in enterohemorrhagic Escherichia coli-associated hemolytic uremic syndrome due to late-emerging sequelae. Clin Infect Dis 54:1413–1421CrossRefPubMed

Gould LH, Demma L, Jones TF, Hurd S, Vugia DJ, Smith K, Shiferaw B, Segler S, Palmer A, Zansky S, Griffin PM (2009) Hemolytic uremic syndrome and death in persons with Escherichia coli O157:H7 infection, foodborne diseases active surveillance network sites, 2000-2006. Clin Infect Dis 49:1480–1485CrossRefPubMed

Loos S, Aulbert W, Hoppe B, Ahlenstiel-Grunow T, Kranz B, Wahl C, Staude H, Humberg A, Benz K, Kranse M, Pohl M, Liebau MC, Schild R, Lemke J, Beringer O, Müller D, Härtel C, Wigger M, Vester U, Konrad M, Haffner D, Pape L, Oh J, Kemper MJ (2017) Intermediate follow-up of pediatric patients with hemolytic uremic syndrome during the 2011 outbreak caused by E.coli O104:H4. Clin Infect Dis 64:1637–1643CrossRefPubMed

Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI (2000) The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 342:1930–1936CrossRefPubMedPubMedCentral

Mody RK, Gu W, Griffin PM, Jones TF, Rounds J, Shiferaw B, Tobin-D’Angelo M, Smith G, Spina N, Hurd S, Lathrop S, Palmer A, Boothe E, Luna-Gierke RE, Hoekstra RM (2015) Postdiarrheal hemolytic uremic syndrome in United States children: clinical spectrum and predictors of in-hospital death. J Pediatr 166:1022–1029CrossRefPubMed

Menne J, Nitschke M, Stingele R, Abu-Tair M, Beneke J, Bramstedt J, Bremer JP, Brunkhorst R, Busch V, Dengler R, Deuschl G, Fellermann K, Fickenscher H, Gerigk C, Goettsche A, Greeve J, Hafer C, Hagenmüller F, Haller H, Herget-Rosenthal S, Hertenstein B, Hofmann C, Lang M, Kielstein JT, Klostermeier UC, Knobloch J, Kuehbacher M, Kunzendorf U, Lehnert H, Manns MP, Menne TF, Meyer TN, Michael C, Münte T, Neumann-Grutzeck C, Nuernberger J, Pavenstaedt H, Ramazan L, Renders L, Repenthin J, Ries W, Rohr A, Rump LC, Samuelsson O, Sayk F, Schmidt BMW, Schnatter S, Schöcklmann H, Schreiber S, von CU S, Steinhoff J, Stracke S, Suerbaum S, van de Loo A, Vischedyk M, Weissenborn K, Wellhöner P, Wiesner M, Zeissig S, Büning J, Schiffer M, Kuehbacher T (2012) EHEC-HUS consortium: validation of treatment strategies for enterohaemorrhagic Escherichia coli O104:H4 induced haemolytic uraemic syndrome: case-control study. BMJ 345:e4565–e4565CrossRefPubMedPubMedCentral

Seifert ME, Tarr PI (2012) Azithromycin decolonization of STEC—a new risk emerges. Nat Rev Nephrol 8:429–429CrossRefPubMed

Nitschke M, Sayk F, Härtel C, Roseland RT, Hauswaldt S, Steinhoff J, Fellermann K, Derad I, Wellhöner P, Büning J, Tiemer B, Katalinic A, Rupp J, Lehnert H, Solbach W, Knobloch JK-M (2012) Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. JAMA 307:1046–1052CrossRefPubMed

Tarr PI, Sadler JE, Chandler WL, George JN, Tsai H-M (2012) Should all adult patients with diarrhoea-associated HUS receive plasma exchange? Lancet 379:516 author reply 516–517 CrossRefPubMed

10.

McMinn JR, Thomas IA, Terrell DR, Duvall D, Vesely SK, George JN (2003) Complications of plasma exchange in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: a study of 78 additional patients. Transfusion 43:415–416CrossRefPubMed

11.

Greinacher A, Friesecke S, Abel P, Dressel A, Stracke S, Fiene M, Ernst F, Selleng K, Weissenborn K, Schmidt BMW, 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 haemolytic uraemic syndrome: a prospective trial. Lancet 378:1166–1173CrossRefPubMed

12.

Roukens AH, Vandenbroucke JP (2012) Immunoadsorption in patients with haemolytic uraemic syndrome. Lancet 379:517 author reply 518–519 CrossRefPubMed

13.

Schrezenmeier H, Höchsmann B (2012) Drugs that inhibit complement. Transfus Apher Sci 46:87–92CrossRefPubMed

14.

Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361:1676–1687CrossRefPubMed

15.

Noris M, Mescia F, Remuzzi G (2012) STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 8:622–633CrossRefPubMed

16.

Kaplan BS, Thomson PD, MacNab GM (1973) Letter: serum-complement levels in haemolytic-uraemic syndrome. Lancet 2:1505–1506CrossRefPubMed

17.

Cameron JS, Vick R (1973) Letter: plasma-C3 in haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura. Lancet 2:975CrossRefPubMed

18.

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 4:1920–1924CrossRefPubMedPubMedCentral

19.

Orth D, Khan AB, Naim A, Grif K, Brockmeyer J, Karch H, Joannidis M, Clark SJ, Day AJ, Fidanzi S, Stoiber H, Dierich MP, Zimmerhackl LB, Würzner R (2009) Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome. J Immunol 182:6394–6400CrossRefPubMed

20.

Ståhl A-L, Sartz L, Karpman D (2011) Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Blood 117:5503–5513CrossRefPubMed

21.

Morigi M, Galbusera M, Gastoldi S, Locatelli M, Buelli S, Pezzotta A, Pagani C, Noris M, Gobbi M, Stravalaci M, Rottoli D, Tedesco F, Remuzzi G, Zoja C (2011) Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J Immunol 187:172–180CrossRefPubMed

22.

Legendre CM, Licht C, Loirat C (2013) Eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 369:1379–1380PubMed

23.

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

24.

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 Shiga toxin-producing Escherichia coli O104:H4 hemolytic uremic syndrome in Germany: presentation and short-term outcome in children. Clin Infect Dis 55:753–759CrossRefPubMed

25.

Kemper MJ (2012) Outbreak of hemolytic uremic syndrome caused by E. coli O104:H4 in Germany: a pediatric perspective. Pediatr Nephrol 27:161–164CrossRefPubMed

26.

Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637CrossRefPubMedPubMedCentral

27.

Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL (2007) Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 71:1028–1035CrossRefPubMed

28.

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 55:758–765PubMed

29.

Ferraris JR, Ferraris V, Acquier AB, Sorroche PB, Saez MS, Ginaca A, Mendez CF (2015) Activation of the alternative pathway of complement during the acute phase of typical haemolytic uraemic syndrome. Clin Exp Immunol 181:118–125CrossRefPubMedPubMedCentral

30.

Delmas Y, Vendrely B, Clouzeau B, Bachir H, Bui H-N, 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 haemolytic uraemic syndrome in France: outcome with eculizumab. Nephrol Dial Transplant 29:565–572CrossRefPubMed

31.

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 (Baltimore) 94:e1000CrossRefPubMed

32.

Donnerstag F, Ding X, Pape L, Bültmann E, Lücke T, Zajaczek J, Hoy L, Das AM, Lanfermann H, Ehrich J, Hartmann H (2012) Patterns in early diffusion-weighted MRI in children with haemolytic uraemic syndrome and CNS involvement. Eur Radiol 22:506–513CrossRefPubMed

33.

Oakes RS, Kirkham JK, Kirkhamm JK, Nelson RD, Siegler RL (2008) Duration of oliguria and anuria as predictors of chronic renal-related sequelae in post-diarrheal hemolytic uremic syndrome. Pediatr Nephrol 23:1303–1308CrossRefPubMed

34.

Dinh A, Anathasayanan A, Rubin LM (2015) Safe and effective use of eculizumab in the treatment of severe Shiga toxin Escherichia coli-associated hemolytic uremic syndrome. Am J Health Syst Pharm 72:117–120CrossRefPubMed

35.

Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, Delmas Y, Douglas K, Furman RR, Gaber OA, Goodship T, Herthelius M, Hourmant M, Legendre CM, Remuzzi G, Sheerin N, Trivelli A, Loirat C (2015) Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int 87:1061–1073CrossRefPubMedPubMedCentral

36.

Noris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E, Tripodo C, Bettoni S, Donadelli R, Valoti E, Tedesco F, Amore A, Coppo R, Ruggenenti P, Gotti E, Remuzzi G (2014) Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 124:1715–1726CrossRefPubMedPubMedCentral

37.

Ahlenstiel-Grunow T, Hachmeister S, Bange FC, Wehling C, Kirschfink M, Bergmann C, Pape L (2016) Systemic complement activation and complement gene analysis in enterohaemorrhagic Escherichia coli-associated paediatric haemolytic uraemic syndrome. Nephrol Dial Transplant 31:1114–1121CrossRefPubMed

38.

ClinicalTrials.gov [Internet]. Garnier A: University hospital of Toulouse (Fr), 2014 July 28 – identifier: NCT02205541, Eculizumab in Shiga-toxin Related Hemolytic and Uremic Syndrome Pediatric Patients—ECULISHU [cited, Jan 11, 2017]. Available from: https://clinicaltrials.gov/ct2/show/NCT02205541

Title: Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study
Authors: Lucas Percheron
Raluca Gramada
Stéphanie Tellier
Remi Salomon
Jérôme Harambat
Brigitte Llanas
Marc Fila
Emma Allain-Launay
Anne-Laure Lapeyraque
Valerie Leroy
Anne-Laure Adra
Etienne Bérard
Guylhène Bourdat-Michel
Hassid Chehade
Philippe Eckart
Elodie Merieau
Christine Piètrement
Anne-Laure Sellier-Leclerc
Véronique Frémeaux-Bacchi
Chloe Dimeglio
Arnaud Garnier
Publication date: 01-08-2018
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 8/2018
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-018-3903-9

At a glance: The STEP trials

Springer Medicine

Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 8/2018

Infections and the kidney: a tale from the tropics

Using dynamic treatment regimes to understand erythropoietin-stimulating agent hyporesponsiveness

Renal, auricular, and ocular outcomes of Alport syndrome and their current management

Acquired thrombotic thrombocytopenic purpura with isolated CFHR3/1 deletion—rapid remission following complement blockade

Clinical value of ambulatory blood pressure in pediatric patients after renal transplantation

The role of von Willebrand factor in thrombotic microangiopathy