Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study
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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.
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).
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.
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.
KeywordsHemolytic uremic syndrome Acute kidney injury Pediatric Complement
Compliance with ethical standards
All parents gave informed consent for their children. The National Code on Clinical Trials has declared that ethics approval is not necessary for retrospective studies.
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.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 54:1413–1421CrossRefPubMedGoogle Scholar
- 2.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 49:1480–1485CrossRefPubMedGoogle Scholar
- 3.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 64:1637–1643CrossRefPubMedGoogle Scholar
- 5.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 166:1022–1029CrossRefPubMedGoogle Scholar
- 6.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–e4565CrossRefPubMedPubMedCentralGoogle Scholar
- 8.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 307:1046–1052CrossRefPubMedGoogle Scholar
- 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 378:1166–1173CrossRefPubMedGoogle Scholar
- 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 4:1920–1924CrossRefPubMedPubMedCentralGoogle Scholar
- 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 182:6394–6400CrossRefPubMedGoogle Scholar
- 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 187:172–180CrossRefPubMedGoogle Scholar
- 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 55:753–759CrossRefPubMedGoogle Scholar
- 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 55:758–765PubMedGoogle Scholar
- 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 29:565–572CrossRefPubMedGoogle Scholar
- 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 87:1061–1073CrossRefPubMedPubMedCentralGoogle Scholar
- 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 124:1715–1726CrossRefPubMedPubMedCentralGoogle Scholar
- 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 31:1114–1121CrossRefPubMedGoogle Scholar
- 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