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

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 Bneurological 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).

Case-management protocol for bloody diarrhea as a model to reduce the clinical impact of Shiga toxin-producing Escherichia coli infections. Experience from Southern Italy

“…In two of these cases, neurological involvement was ascertained by clinical neurological evaluation, electrophysiological investigation (EEGs), and/or magnetic resonance imaging (MRI) of the brain. For these patients, eculizumab was administered after obtaining signed informed consent from the parents for "off-label" use of this drug [16]. All children with HUS showed a complete clinical recovery.…”

“…It has been shown that 10-15% of patients with a STEC infection (mostly E. coli O157:H7) develop HUS after a median interval of 7 days from the onset of diarrhea [10,17,18]. Therefore, there is an opportunity to intervene to reduce the risk of developing HUS and/or avoiding sequelae such as neurological involvement through appropriate clinical management of the cases [16,18]. Although there is a lack of specific therapy for STEC infection, when urine flow is preserved, early vigorous volume expansion reduces the risk of HUS and improves the short-and long-term outcomes [11,12].…”

“…Although there is a lack of specific therapy for STEC infection, when urine flow is preserved, early vigorous volume expansion reduces the risk of HUS and improves the short-and long-term outcomes [11,12]. This formed the basis of our organizational model, which focused on prompt hospitalization of children with BD and early detection of STEC infection in the pediatric population [16,18]. Moreover, re-evaluation of the laboratory parameters after 12/24 h, according to the protocol, is strongly recommended to monitor the possible evolution into HUS, which can occur rapidly [10].…”

“…Of the 53 STEC children, four cases (7.5%) evolved into HUS despite a prompt STEC diagnosis, but all HUS cases had a favorable clinical outcome, including two cases that showed neurological involvement and were treated with eculizumab [16]. It should be noted that two of the four HUS cases (twins) were due to STEC O26, which may be particular virulent toward young children [15], and that in one of the other two non-O26 cases, an antibiotic was administered before hospitalization.…”

Síndrome Hemolítico Urémico asociado a Shigatoxina: ¿Cómo prevenirlo?

“…La plasmaféresis o la infusión de plasma fresco congelado en SHU STx (+) 21,22 es aún debatido y su eficacia no es apoyada por estudios randomizados, como si ocurre en otras MAT (SHU atípico, púrpura trombocitopénico trombótico adquirido) 23,24 . De la misma manera, el uso de eculizumab, un anticuerpo monoclonal humanizado que detiene la cascada del complemento bloqueando el clivaje de C5, ha demostrado su utilidad en el SHU atípico por defectos genéticos o adquiridos de inhibidores de la cascada del complemento, pero en el caso del SHU STx(+) su eficacia no ha sido concluyentemente demostrada hasta el momento 25 , aunque sí parece tener cierta utilidad en disminuir las consecuencias neurológicas de esta patología 26 .…”