The Czech Experience with Eculizumab in Severe Paediatric Shiga Toxin-Producing Escherichia coli-Associated Haemolytic Uremic Syndrome Patients
Abstract
Haemolytic uremic syndrome (HUS) is characterised by acute kidney injury (AKI), non-immune microangiopathic haemolytic anaemia and thrombocytopenia. Shiga toxin-producing Escherichia coli-associated HUS (STEC-HUS) accounts for 90% of all HUS cases in children, and represents the most common primary disease causing AKI in children.
E. Coli O157 is the most frequent serotype that causes STEC-HUS in Europe and North America, but only 10% of patients exposed to STEC develop HUS.
The clinical course of the condition varies from mild to severe, with life-threatening complications. Approximately 50% of patients require renal replacement therapy (RRT) (Sheerin NS et al., F1000Res 2019; 8).
The mortality rate is <5%, and is mainly caused by neurological involvement associated with poor outcomes, and is the most frequent extra-renal complication. Neurological severity varies significantly from nonspecific headaches to coma.
The pathophysiological mechanisms leading to central nervous system involvement include electrolyte abnormalities, hypertension, uraemia, local microangiopathy and direct toxic effects in brain tissue (Zieg J et al., Pediatr Int 2012; 54: 166 -167). Other organ complications may also include cardiac, gastrointestinal and musculoskeletal systems.
Although renal outcomes have improved, a significant proportion of affected individuals (25-40%) still suffer with permanent kidney damage - proteinuria, hypertension and chronic kidney disease (Sheerin NS et al., F1000Res 2019; 8). STEC-HUS pathogenesis is complex.
Initially, a patient is infected by STEC from contaminated food or water, or alternatively by direct contact with faeces from infected animals or people. After intestinal colonisation, STEC may produce Shiga toxins (Stx), which enter the circulation.
After binding to specific receptors (mainly Gb3 receptors), the complex induces endothelial injury and organ damage via cell apoptosis and inflammation. Gb3 receptors are located also in the cerebral vascular endothelium.
There is a growing body of evidence suggesting complement activation during STEC-HUS; Stx was shown to bind regulator proteins of the alternative complement pathway, mainly factor H (Orth D et al., J Immunol 2009; 182: 6394-6400). Further studies have observed complement break-down products on blood cell surfaces, and that patients with complement activation suffer a more severe disease course (Karnisova L et al., Eur J Pediatr 2018; 177: 1837-1844).
Therefore, eculizumab, a monoclonal antibody that targets complement protein C5, became a potentional novel therapy for children with STEC-HUS.