A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement
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.
KeywordsHemolytic uremic syndrome Neurological involvement Eculizumab Magnetic resonance imaging
Compliance with ethical standards
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.
- 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.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.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
- 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.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
- 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
- 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.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.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.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
- 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.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
- 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
- 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
- 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
- 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.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.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
- 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.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.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.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.Ward DM (2011) Conventional apheresis therapies: a review. J ClinApher 26:230–238Google 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 378:1166–1173CrossRefGoogle 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:e1000Google Scholar