Particulate Shiga Toxin 2 in Blood is Associated to the Development of Hemolytic Uremic Syndrome in Children

Maurizio Brigotti; Xiaohua He; Domenica Carnicelli; Valentina Arfilli; Elisa Porcellini; Elisabetta Galassi; Pier Luigi Tazzari; Francesca Ricci; Stephanie A. Patfield; Sara Testa; Fabio Paglialonga; Damiano Picicco; Alfredo Caprioli; Gaia Scavia; Stefano Morabito; Gianluigi Ardissino

doi:10.1055/s-0039-3400301

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2020; 120(01): 107-120
DOI: 10.1055/s-0039-3400301

Blood Cells, Inflammation and Infection

Georg Thieme Verlag KG Stuttgart · New York

Particulate Shiga Toxin 2 in Blood is Associated to the Development of Hemolytic Uremic Syndrome in Children

Maurizio Brigotti

¹Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

,

Xiaohua He

²Agricultural Research Service, Western Regional Research Center, U.S. Department of Agriculture, Albany, California, United States

,

Domenica Carnicelli

¹Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

,

Valentina Arfilli

¹Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

,

Elisa Porcellini

¹Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

,

Elisabetta Galassi

¹Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

,

Pier Luigi Tazzari

³Immunohematology and Transfusion Center, S. Orsola-Malpighi Hospital, Bologna, Italy

,

Francesca Ricci

³Immunohematology and Transfusion Center, S. Orsola-Malpighi Hospital, Bologna, Italy

,

Stephanie A. Patfield

²Agricultural Research Service, Western Regional Research Center, U.S. Department of Agriculture, Albany, California, United States

,

Sara Testa

⁴Center for HUS Prevention Control and Management, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

,

Fabio Paglialonga

⁴Center for HUS Prevention Control and Management, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

,

Damiano Picicco

⁴Center for HUS Prevention Control and Management, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

,

Alfredo Caprioli

⁵European Reference Laboratory for Escherichia coli, Istituto Superiore di Sanità, Rome, Italy

,

Gaia Scavia

⁵European Reference Laboratory for Escherichia coli, Istituto Superiore di Sanità, Rome, Italy

,

Stefano Morabito

⁵European Reference Laboratory for Escherichia coli, Istituto Superiore di Sanità, Rome, Italy

,

Gianluigi Ardissino

⁴Center for HUS Prevention Control and Management, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

› Author Affiliations

Abstract

Hemolytic uremic syndrome (HUS), the leading cause of acute renal failure in children (< 3 years), is mainly related to Shiga toxins (Stx)-producing Escherichia coli (STEC) infections. STEC are confined to the gut resulting in hemorrhagic colitis, whereas Stx are delivered in blood to target kidney and brain, with unclear mechanisms, triggering HUS in 5 to 15% of infected children. Stx were found on circulating cells, free in sera (soluble Stx) or in blood cell-derived microvesicles (particulate Stx), whereby the relationship between these forms of circulating toxins is unclear. Here, we have examined 2,846 children with bloody diarrhea and found evidence of STEC infection in 5%. Twenty patients were enrolled to study the natural course of STEC infections before the onset of HUS. In patients, Stx were found to be associated to circulating cells and/or free and functionally active in sera. In most children, Stx were bound to neutrophils when high amounts of toxins were found in feces. Time-course analysis showed that Stx increased transiently in patients' sera while the decrease of toxin amount on leukocytes was observed. Notably, patients who recovered (85%) displayed different settings than those who developed HUS (15%). The distinctive feature of the latter group was the presence in blood of particulate Stx2 (Stx2 sedimented at g-forces corresponding to 1 μm microvesicles) the day before diagnosis of HUS, during the release phase of toxins from circulating cells. This observation strongly suggests the involvement of blood cell-derived particulate Stx2 in the transition from hemorrhagic colitis to HUS.

Keywords

hemolytic uremic syndrome - Shiga toxin-producing Escherichia coli - bloody diarrhea - bacterial toxins

Full Text

References

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Supplementary Material

Supplementary Material