Safe and effective use of eculizumab in the treatment of severe Shiga toxin<i>Escherichia coli</i>-associated hemolytic uremic syndrome

Dinh, Alex; Anathasayanan, Ashok; Rubin, Lisa M.

doi:10.2146/ajhp140134

Cited by 15 publications

(10 citation statements)

References 14 publications

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“…On the other hand, enhanced plasmin generation and fibrinolysis, as expected in the Cpb2 −/− mice and supported by the higher levels of D‐dimer, should lead to a decreased clot burden and a beneficial effect in these mice, rather than increased disease susceptibility; thus, fibrin is probably not a key substrate in this model. Eculizumab is an anti‐human C5 antibody with an equivalent mode of action to the anti‐mouse C5 antibody used in our studies and has been shown to have beneficial effects in Shiga toxin‐producing E. coli infections, especially when administered early .…”

Section: Discussionmentioning

confidence: 99%

Carboxypeptidase B2 and N play different roles in regulation of activated complements C3a and C5a in mice

Morser

Shao

Nishimura

et al. 2018

Journal of Thrombosis and Haemostasis

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Background There are two basic carboxypeptidases in plasma. Carboxypeptidase B2 (CPB2) is activated from a circulating zymogen, proCPB2, and carboxypeptidase N (CPN) is constitutively active with both inactivating complement C3a and C5a. Aims To test the roles of CPB2 and CPN in complement-driven mouse models of cobra venom factor (CVF) challenge and hemolytic-uremic syndrome (HUS). Methods Cpb2 , Cpn and wild-type (WT) mice were compared in an HUS model induced by Shiga toxin and lipopolysaccharide administration and following CVF administration. Results HUS was exacerbated in Cpb2 mice more than in Cpn mice, compared with WT mice. Cpb2 mice developed the HUS clinical triad of microangiopathic hemolytic anemia, uremia and thrombocytopenia. Treatment with anti-C5 antibody improved survival of both Cpb2 and Cpn mice. In contrast, when challenged acutely with CVF, the reverse phenotype was observed. Cpn mice had markedly worse disease than Cpb2 mice, whereas the WT mice were resistant. Conclusions CPN and CPB2 play overlapping but non-redundant roles in regulating complement activation in vivo. The constitutively active CPN is key for inactivation of systemic C5a, whereas CPB2 functions as an on-demand supplementary anaphylatoxin inhibitor in inactivating excessive C5a formed locally.

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Section: Discussionmentioning

confidence: 99%

Carboxypeptidase B2 and N play different roles in regulation of activated complements C3a and C5a in mice

Morser

Shao

Nishimura

et al. 2018

Journal of Thrombosis and Haemostasis

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“…Los resultados de este tratamiento en niños con compromiso neurológico severo por SHU+D aún son inciertos, por lo que es necesario evaluar crí-ticamente los resultados de los estudios que se llevan a cabo en la actualidad antes de recomendar su uso [7][8][9][10]22 .…”

Section: Discussionunclassified

“…Todos deben detectarse y tratarse precozmente incluyendo diálisis en falla renal aguda. No obstante, la plasmaféresis y el uso de antagonistas de proteínas del complemento podrían ser alternativas frente al compromiso severo del SNC [7][8][9][10] .…”

Section: Introductionunclassified

Compromiso cerebrovascular agudo en síndrome hemolítico urémico: descripción de dos casos pediátricos

López

Huete

Hernández

2017

Rev. chil. pediatr.

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Palabras clave:Ictus en pediatría, insuficiencia renal aguda, microangiopatía trombótica, discapacidad, Síndrome Hemolítico Urémico ResumenIntroducción: El Síndrome Hemolítico Urémico asociado a diarrea (SHU+D) es un desorden multisistémico en el cual el compromiso neurológico se asocia a empeoramiento del pronóstico. Una causa importante de daño neurológico permanente es el compromiso cerebrovascular. Objetivo: Reportar dos casos pediátricos de SHU+D con compromiso neurológico severo debido a patología cerebrovascular y revisar la literatura disponible. Casos clínicos: Dos niños de 15 y 21 meses, previamente sanos, debutaron con convulsiones y compromiso de conciencia dentro de la primera semana de un SHU+D. Ambos presentaron hipertensión, falla renal aguda severa y déficit motor focal. Un niño mejoró significativamente su estado neurológico después de cinco sesiones de plasmaféresis. La resonancia magnética encefálica, mostró en el primer niño infartos bilaterales múltiples de vasos pequeños y lesiones de sustancia blanca. En el segundo paciente se identificaron extensos infartos bilaterales en territorios de ambas arterias cerebrales medias. Al año del evento agudo, ambos niños con déficit funcional marcado; el primer paciente evolucionó con retraso del desarrollo del lenguaje y hemiparesia espástica; el segundo persistió con cuadriparesia espástica, epilepsia con mal control de crisis y marcado deterioro funcional. Conclusión: Aunque la mayoría de los niños con SHU+D y compromiso cerebral no presentan secuelas a largo plazo, la patología cerebrovascular en el período agudo puede causar daño permanente, por lo que, además del manejo de las alteraciones hidroelectrolíticas, hipertensión y falla renal, las terapias dirigidas a mecanismos fisiopatológicos específicos desencadenantes del compromiso vascular podrían mejorar el pronóstico. 641 CASO CLínICO IntroducciónEl síndrome hemolítico urémico asociado a diarrea (SHU+D) es una patología multisistémica y la primera causa de falla renal aguda en niños menores de 4 años. Es gatillado en forma primaria por una infección gastrointestinal, cuyo agente etiológico más frecuentemente implicado es la Escherichia Coli Enterohemorrágica (ECEH) productora de shigatoxina (Stx) serotipo O157:H7. La triada de falla renal aguda, anemia hemolítica y trombocitopenia es distintiva y constituye la base del diagnóstico. La fisiopatología subyacente tiene como eje central el desarrollo de una microangiopatía trombótica que desencadena un desorden multisistémico con alteraciones hemodinámicas que pueden comprometer el sistema nervioso central (SNC) además de tractos gastrointestinales, páncreas, hígado y riñón [1][2][3][4] .El compromiso neurológico asociado al SHU+D, ocurre en el 35 a 50% de los casos. En su patogé-nesis influyen la disfunción endotelial (mediada por la activación de la cascada del complemento inducida por la Stx), la hipertensión arterial y alteraciones hidroelectrolíticas (frecuentemente hiponatremia). Las diversas manifestaciones clínicas pueden revertir parcial ...

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“…Purified C1 inhibitor is indicated for the treatment of hereditary or acquired C1 inhibitor deficiency. A humanized monoclonal antibody, eculizumab, has been used for several years to treat paroxysmal nocturnal hemoglobinuria (PNH) and more recently has been used successfully in several cases of shiga-toxin associated hemolytic uremic syndrome (Delmas, et al, 2014, Dinh, et al, 2015, Lapeyraque, et al, 2011). Other products in various stages of development include: antibodies or fragments of antibodies directed against C5, factor D, C1s or MASP-2; small molecules that block factor D, C5aR or C3 or soluble complement inhibitors of complement (CR1 or fragments of FH).…”

Section: Introductionmentioning

confidence: 99%

Utilizing complement evasion strategies to design complement-based antibacterial immunotherapeutics: Lessons from the pathogenic Neisseriae

et al. 2016

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Novel therapies are urgently needed to combat the global threat of multidrug-resistant pathogens. Complement forms an important arm of innate defenses against infections. In physiological conditions, complement activation is tightly controlled by soluble and membrane-associated complement inhibitors, but must be selectively activated on invading pathogens to facilitate microbial clearance. Many pathogens, including Neisseria gonorrhoeae and N. meningitidis, express glycans, including N-acetylneuraminic acid (Neu5Ac), that mimic host structures to evade host immunity. Neu5Ac is a negatively charged 9-cabon sugar that inhibits complement, in part by enhancing binding of the complement inhibitor factor H (FH) through C-terminal domains (19 and 20) on FH. Other microbes also bind FH, in most instances through FH domains 6 and 7 or 18-20. Here we describe two strategies to target complement activation on Neisseriae. First, microbial binding domains of FH were fused to IgG Fc to create FH18-20/Fc (binds gonococci) and FH6,7/Fc (binds meningococci). A point mutation in FH domain 19 eliminated hemolysis caused by unmodified FH18-20, but retained binding to gonococci. FH18-20/Fc and FH6,7/Fc mediated complement-dependent killing in vitro and showed efficacy in animal models of gonorrhea and meningococcal bacteremia, respectively. The second strategy utilized CMP-nonulosonate (CMP-NulO) analogs of sialic acid that were incorporated into LOS and prevented complement inhibition by physiologic CMP-Neu5Ac and resulted in attenuated gonococcal infection in mice. While studies to establish the safety of these agents are needed, enhancing complement activation on microbes may represent a promising strategy to treat antimicrobial resistant organisms.

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Safe and effective use of eculizumab in the treatment of severe Shiga toxinEscherichia coli-associated hemolytic uremic syndrome

Abstract: An 18-year-old man who developed severe HUS due to STEC O121 and was unresponsive to traditional supportive therapies was successfully treated with eculizumab.

Cited by 15 publications

References 14 publications

Carboxypeptidase B2 and N play different roles in regulation of activated complements C3a and C5a in mice

Carboxypeptidase B2 and N play different roles in regulation of activated complements C3a and C5a in mice

Compromiso cerebrovascular agudo en síndrome hemolítico urémico: descripción de dos casos pediátricos

Utilizing complement evasion strategies to design complement-based antibacterial immunotherapeutics: Lessons from the pathogenic Neisseriae

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