Influence of socio-economic status on Shiga toxin-producing Escherichia coli (STEC) infection incidence, risk factors and clinical features.

Shiga toxin-producing Escherichia coli (STEC) infection can cause serious illness including haemolytic uraemic syndrome. The role of socio-economic status (SES) in differential clinical presentation and exposure to potential risk factors amongst STEC cases has not previously been reported in England. We conducted an observational study using a dataset of all STEC cases identified in England, 2010-2015. Odds ratios for clinical characteristics of cases and foodborne, waterborne and environmental risk factors were estimated using logistic regression, stratified by SES, adjusting for baseline demographic factors. Incidence was higher in the highest SES group compared to the lowest (RR 1.54, 95% CI 1.19-2.00). Odds of Accident and Emergency attendance (OR 1.35, 95% CI 1.10-1.75) and hospitalisation (OR 1.71, 95% CI 1.36-2.15) because of illness were higher in the most disadvantaged compared to the least, suggesting potential lower ascertainment of milder cases or delayed care-seeking behaviour in disadvantaged groups. Advantaged individuals were significantly more likely to report salad/fruit/vegetable/herb consumption (OR 1.59, 95% CI 1.16-2.17), non-UK or UK travel (OR 1.76, 95% CI 1.40-2.27; OR 1.85, 95% CI 1.35-2.56) and environmental exposures (walking in a paddock, OR 1.82, 95% CI 1.22-2.70; soil contact, OR 1.52, 95% CI 2.13-1.09) suggesting other unmeasured risks, such as person-to-person transmission, could be more important in the most disadvantaged group.

Global and regional source attribution of Shiga toxin-producing Escherichia coli infections using analysis of outbreak surveillance data.

Shiga toxin-producing Escherichia coli (STEC) infections pose a substantial health and economic burden worldwide. To target interventions to prevent foodborne infections, it is important to determine the types of foods leading to illness. Our objective was to determine the food sources of STEC globally and for the six World Health Organization regions. We used data from STEC outbreaks that have occurred globally to estimate source attribution fractions. We categorised foods according to their ingredients and applied a probabilistic model that used information on implicated foods for source attribution. Data were received from 27 countries covering the period between 1998 and 2017 and three regions: the Americas (AMR), Europe (EUR) and Western-Pacific (WPR). Results showed that the top foods varied across regions. The most important sources in AMR were beef (40%; 95% Uncertainty Interval 39-41%) and produce (35%; 95% UI 34-36%). In EUR, the ranking was similar though with less marked differences between sources (beef 31%; 95% UI 28-34% and produce 30%; 95% UI 27-33%). In contrast, the most common source of STEC in WPR was produce (43%; 95% UI 36-46%), followed by dairy (27%; 95% UI 27-27%). Possible explanations for regional variability include differences in food consumption and preparation, frequency of STEC contamination, the potential of regionally predominant STEC strains to cause severe illness and differences in outbreak investigation and reporting. Despite data gaps, these results provide important information to inform the development of strategies for lowering the global burden of STEC infections.

Shiga toxin-induced haemolytic uraemic syndrome and the role of antibiotics: a global overview.

OBJECTIVES: The administration of antibiotics in infections caused by Shiga toxin producing E. coli (STEC) strains, such as O157:H7, was and remains controversial, as it has been associated with the development of haemolytic uraemic syndrome (HUS). We conducted a literature review to better examine this association. METHODS: We searched the PubMed and Google Scholar databases for relevant articles, using the key words: ``haemolytic uraemic syndrome'', ``Shiga toxin'', ``E. coli O157:H7'', ``E. coli O104:H4'', ``STEC colitis'', ``STEC antibiotics'', ``STEC fosfomycin'', ``STEC trimethoprim sulfamethoxazole'', ``STEC fluoroquinolones'', ``STEC ciprofloxacin'', ``STEC rifaximin'', ``STEC gentamycin'', ``STEC colistin'', "Shiga toxin binding agent", "Shiga toxin monoclonal antibody" and ``STEC Japan epidemic''. RESULTS: Numerous studies report that antibiotics increase the risk of HUS development, while others report that antibiotics do not have any effect or can even reduce the rate of HUS development in STEC infections. The infecting STEC strain, the type of antibiotic as well as the timing of its administration appear to significantly affect the development of HUS in a STEC infected patient. CONCLUSIONS: It appears that, while some antibiotics such as b-lactams and TMP/SMX may be detrimental, others appear to be safe and can prevent the development of HUS. Of note, fosfomycin appears to be the antibiotic with the most positive results from clinical studies, and may be able to avert HUS development, especially if administered within the first two or three days from diarrhoea onset. Fluoroquinolones have also shown positive outcomes in clinical studies, despite demonstrating unfavourable results in in vitro studies. Other agents, such as colistin, gentamycin and rifamycins, have shown promising results in in vitro studies and require further evaluation.

Shiga Toxin as a Potential Trigger of CFHR1 Deletion-Associated Thrombotic Microangiopathy.

Thrombotic microangiopathy (TMA) may result from a variety of clinical conditions, including thrombotic thrombocytopenic purpura, Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome and complement-mediated hemolytic uremic syndrome. Thrombocytopenic purpura is diagnosed when ADAMTS13 is <10%, while a diagnosis of Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome is made with the evidence of infection by Shiga toxin-producing Escherichia coli. Diagnosis of complement-mediated hemolytic uremic syndrome is not dependent on a specific laboratory test and is a diagnosis of exclusion. TMA is a rare disease and finding individuals that have more than 1 concurrent etiology leading to TMA is even more rare. Here we describe the presentation and management of an individual with CFHR1 deletion-associated TMA also found to have a positive stool Shiga toxin. We discuss the significance of Shiga toxin in serving as a trigger for development of TMA in an individual predisposed to development of TMA due to presence of a homozygous deletion in CFHR1.

A simple prognostic index for Shigatoxin-related hemolytic uremic syndrome at onset: data from the ItalKid-HUS network.

Shigatoxin Escherichia coli-related hemolytic uremic syndrome (eHUS) is a severe thrombotic microangiopathy (TMA) burdened by life-threatening complications and long-term sequelae. Since hemoconcentration is associated with worse outcome, we tried to develop a reliable and easy-to-calculate index for predicting complications and sequelae based on hemoglobin (Hb) at presentation. The first laboratory examinations with signs of TMA in eHUS patients were analyzed in relation to the outcomes with the receiver operating characteristic curves and their areas under the curve (AUC) for Hb and creatinine (sCr). A total of 197 eHUS patients were identified of whom 24% did not have anemia at presentation. Hb level was the best predictor of a poor outcome (AUC 0.67) but the combination of Hb with sCr, in the formula [(Hb in g/dL + (sCr in mg/dL × 2)], showed an even better AUC of 0.75. The described scoring system was also strongly associated and predictive of all complications and health care needs (8% of patients with scoring > 13 died or entered a permanent vegetative state compared with 0% of those with ≤ 13).Conclusion: The presented score is a simple and early predictor of both short- and long-term outcomes and identifies patients who should undergo rapid volume expansion to counteract hemoconcentration, the spreading of microvascular thrombosis, and the consequent increased organ damage. What is Known: • In eHUS, hemoconcentration is associated with worse short- and long-term outcome. • A prognostic index to identify patients at higher risk for complications at presentation is not available. What is New: • We developed a simple and early prognostic index for eHUS outcome with the combination of Hb and sCr at onset, in the following formula [(Hb in g/dL + (sCr in mg/dL × 2)]. • The proposed HUS Severity Score can promptly identify patients with good outcome and those with high risk of worse short- and long-term outcome.

Isolated abducens nerve palsy treated by immunoadsorption in a patient with diarrhea-associated hemolytic uremic syndrome / Parálisis ocular aislada del sexto par craneal tratada con inmunoadsorción en un paciente con síndrome urémico hemolítico asociado a diarrea

Shiga toxin-producing Escherichia coli (STEC) that causes a prodromal hemorrhagic enteritis is the main cause of hemolytic uremic syndrome (HUS) particularly in pediatric patients. It is characterized by acute kidney injury with microangiopathic hemolytic anemia and thrombocytopenia. The kidney and brain are the two major target organs, and neurological involvement is the most frequent cause of mortality. The time delay between bloody diarrhea and neurological symptoms ranges from few days to a month. Neurological disorders include disturbances in cognitive functions, focal neurological signs, epileptic seizures, myoclonus and neuropsychiatric symptoms. Cerebral magnetic resonance imaging reveals various patterns of hyperintensities distributed through cerebral matter or may be totally normal even the patient has severe neurological involvement. Electroencephalography usually show generalized or focal slowing of the background activity, spikes or sharp waves despite being normal in around 20% of patients. We present here an adult male patient referred to our center with requirement of hemodialysis due to diarrhea-associated HUS complicated by acute kidney injury. Later during the course of plasma exchange therapy the patient developed an isolated abducens nerve palsy. Complete renal recovery was achieved by plasma exchange therapy but abducens palsy remedied rescue introduction of immunoglobulin G (IgG) depletion by immunoadsorption

Escherichia coli, productor de toxina Shiga (STEC), que causa una enteritis hemorrágica en fase prodrómica, es la principal causa del síndrome urémico hemolítico (SUH), particularmente, en pacientes pediátricos. Se caracteriza por una lesión renal aguda con anemia hemolítica microangiopática y trombocitopenia. El riñón y el cerebro son los dos órganos principales a los que ataca, y la afectación neurológica es la causa más frecuente de mortalidad. El tiempo que transcurre entre la aparición de diarrea sanguinolenta y los síntomas neurológicos varía entre pocos días y un mes. Los trastornos neurológicos incluyen alteraciones en las funciones cognitivas, signos neurológicos focales, ataques epilépticos, mioclonías y síntomas neuropsiquiátricos. La resonancia magnética de cerebro revela varios patrones de hiperintensidades distribuidas a través de la materia cerebral o puede ser totalmente normal incluso si el paciente tiene un compromiso neurológico severo. El electroencefalograma generalmente muestra una disminución generalizada o focal de la actividad de fondo, picos u ondas agudas, a pesar de ser normal en alrededor del 20% de los pacientes. Presentamos un paciente adulto de sexo masculino, derivado a nuestro centro para ser tratado con hemodiálisis debido a SUH asociado a diarrea, complicado por insuficiencia renal aguda. Luego, durante el transcurso de la terapia de intercambio de plasma, el paciente desarrolló una parálisis ocular aislada del sexto par craneal. Se logró una recuperación renal completa por medio de la terapia de intercambio plasmático; no obstante, la parálisis del nervio motor ocular externo remedió la disminución de la inmunoglobulina G (IgG) mediante el tratamiento de rescate de inmunoadsorción

Serotipos, perfiles de virulencia y subtipos de stx en Escherichia coli productor de toxina Shiga aislados de productos de pollo / Serotypes, virulence profiles and stx subtypes of Shigatoxigenic Escherichia coli isolated from chicken derived products

Shigatoxigenic Escherichia coli (STEC) is a foodborne pathogen that causes hemolytic uremic syndrome (HUS) and the consumption of chicken products has been related to some HUS cases. We performed a non-selective isolation and characterization of STEC strains from retail chicken products. STEC isolates were characterized according to the presence of stx1, stx2, eae, saa and ehxA; stx subtypes and serotypes. Most of them carried stx2, showing subtypes associated with severe human disease. Although reported in other avian species, the stx2f subtype was not detected. The isolates corresponded to different serotypes and some of them, such as O22:H8, O113:H21, O130:H11, O171:H2 and O178:H19, have also been identified among STEC isolated from patients suffering from diarrhea, hemorrhagic colitis, HUS, as well as from cattle. Considering the virulence profiles and serotypes identified, our results indicate that raw chicken products, especially hamburgers sold at butcheries, can be vehicles for high-risk STEC strains.

Escherichia coli productor de toxina de Shiga (STEC) es un patógeno transmitido por alimentos que causa el síndrome urémico hemolítico (SUH). Algunos casos de SUH están relacionados con el consumo de productos de pollo. Se realizó el aislamiento no selectivo y la caracterización de cepas STEC provenientes de productos de pollo atendiendo a la presencia de stx1, stx2, eae, saa y ehxA, subtipos de stx y serotipos. La mayoría de los aislamientos portaba stx2 y subtipos de stx asociados con enfermedades graves en humanos. Aunque se ha detectado en otras especies aviares, el subtipo stx2f no se encontró. Se detectaron diferentes serotipos, entre ellos O22:H8, O113:H21, O130:H11, O171:H2 y O178:H19, también identificados como STEC aislados de pacientes con diarrea, colitis hemorrágica y SUH, y de ganado bovino. Teniendo en cuenta los perfiles de virulencia y los serotipos identificados, nuestros resultados indican que los productos de pollo crudos, especialmente las hamburguesas que se venden en las carnicerías, pueden ser vehículos de cepas STEC de alto riesgo.

Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome.

Hemolytic uremic syndrome is a rare disease, frequently responsible for renal insufficiency in children. Recent findings have led to renewed interest in this pathology. The discovery of new gene mutations in the atypical form of HUS and the experimental data suggesting the involvement of the complement pathway in the typical form, open new perspectives for treatment. This review summarizes the current state of knowledge on both typical and atypical hemolytic uremic syndrome pathophysiology and examines new perspectives for treatment.

Current evidence for the role of complement in the pathogenesis of Shiga toxin haemolytic uraemic syndrome.

Shiga toxin-associated haemolytic uraemic syndrome (Stx HUS) is the leading cause of paediatric acute kidney injury. This toxin-mediated disease carries a significant morbidity and mortality but has no direct treatments. Rare familial atypical HUS (aHUS) is now understood to result from over-activation of the alternative complement pathway causing glomerular endothelial damage. By understanding the pathogenic mechanisms of this disease, the monoclonal antibody eculizumab, which blocks the final common pathway of complement, is now being used to treat aHUS. For this reason, clinicians and scientists are studying the role of the alternative complement pathway in Stx HUS with the aim of targeting treatment in a similar way. There is some evidence suggesting that complement plays a role in the pathogenesis of Stx HUS, but other mechanisms may also be important. Clinically, modulating the complement system using plasma exchange provides no proven benefit in Stx HUS, and the use of eculizumab has provided conflicting results. Understanding the local effect of Stx on the glomerulus, in particular regulation of the complement and coagulation systems, may lead to advances in defining the precise pathogenesis of this disease. Then, targeted treatment strategies could be devised and clinical trials undertaken.

Componentes alimentarios de potencial aplicación en la dietoterapia de enfermedades provocadas por cepas de escherichia coli productoras de toxina tipo shiga / Food components of potential application in the dietoterapia of diseases provoked by vine-stocks of escherichia coli producers of toxin type shiga

En Argentina, Escherichia coli O157:H7 es el serotipo prevalente asociado a grandes brotes y casos esporádicos de colitis hemorrágica y síndrome urémico hemolítico (SUH), siendo el país con mayor tasa de incidencia en el mundo con alrededor de 500 nuevos casos por año. El SUH representa la principal causa de falla renal aguda en la infancia, la segunda causa de falla renal crónica y el 20% de los casos de transplante renal durante la infancia y la adolescencia. Se ha demostrado que la habilidad de la cepa para causar la enfermedad está relacionada a la acción de factores de virulencia implicados en el proceso de colonización del epitelio intestinal con posterior reacción inflamatoria y por la capacidad de secretar toxinas VT1 y VT2 responsables del daño del endotelio vascular con el consecuente desarrollo de SUH. En la presente tesis doctoral se investigó desde la dietoterapia, extractos de origen vegetal y componentes de cepas probióticas potencialmente útiles en la inhibición de la colonización de E. coli O157:H7 a nivel intestinal como medida preventiva, e inhibición de la acción citotóxica de VT sobre células eucariotas. Se determinaron componentes fenólicos obtenidos a partir de la maceración de harina de algarroba (Prosopis alba) y café de mistol (Ziziphus mistol) en distintos solventes (alcohol, agua destilada, acetona y hexano). Los mismos fueron nalizados mediante marcha analítica fitoquímica, cromatografía en capa delgada y cuantificados por espectrofotometría. Por otro lado se obtuvieron componentes de leche fermentada con granos de kéfir.

SUMMARY: In Argentina, Escherichia coli O157:H7 is prevalent serotype associated with large outbreaks and sporadic cases of hemorrhagic colitis and hemolytic uremic syndrome (HUS), being the country with the highest incidence rate in the world with about 500 new cases per year. HUS is the leading cause of acute renal failure in infancy, the second leading cause of chronic renal failure and 20% of cases of renal transplantation during childhood and adolescence. It has been shown that the ability of the strain to cause disease is linked by the action of virulence factors required in the colonization of intestinal epithelium and subsequent inflammatory response and their ability to secrete toxins, VT1 and VT2 responsible for damage to the vascular endothelium with the subsequent development of HUS. In this thesis we investigated plant extracts and components of probiotic strains potentially useful in diet therapy to inhibit the colonization of E. coli O157:H7 in the intestine as a preventive measure, able to interfere the cytotoxic action of VT on eukaryotic cells. Phenolic compounds were identified, they were obtained from plant extracts of P. alba and Z. mistol macerated in different solvents (alcohol, distilled water, acetone and hexane). They were analyzed using phytochemical methods, thin layer chromatography and quantified by spectrophotometry. Furthermore components were obtained from fermented milk kefir grains.

Microparticle generation and leucocyte death in Shiga toxin-mediated HUS.

BACKGROUND: Shiga toxin-induced haemolytic uraemic syndrome (STEC-HUS) is an acute multisystem disorder characterized by renal failure, neurological dysfunction, haemolysis and intravascular thrombosis. Circulating microparticles originating from a number of cell types including thrombocytes and leucocytes are elevated in paediatric patients. In vitro data also suggest modification of leucocyte death by Shiga toxin. Here, we investigated microparticle generation and leucocyte cell death in vivo in adult STEC-HUS patients during acute disease and recovery. METHODS: Multi-colour flow cytometry and immunofluorescence were used to assess microparticle concentration and provenience thrombocyte microparticle seeding to leucocytes and leucocyte cell death in adult STEC-HUS patients treated at a tertiary care centre during the STEC-HUS outbreak in Germany in 2011. RESULTS: Plasma microparticle concentrations of both platelet and leucocyte origin were elevated during acute STEC-HUS. Platelet microparticles (MP) were detected on a high proportion of monocytes and granulocytes. Among therapeutic interventions, plasma exchange reduced platelet marker expression on leucocytes, inhibition of complement had only moderate impact on the number of circulating MP and did not alter platelet microparticle binding to leucocytes. Numbers of apoptotic and necrotic monocytes and granulocytes were significantly increased in patients with STEC-HUS compared to healthy controls. Complement inhibition significantly increased the number of circulating apoptotic cells. Monocyte apoptosis on admission was significantly higher in patients subsequently assigned to plasma exchange or admitted to the intensive care unit. CONCLUSIONS: In STEC-HUS, elevated numbers of circulating MP and dead leucocytes were detected. Monocyte and granulocyte deaths are novel markers of acute STEC-HUS that may actively contribute to tissue destruction by liberation of pro-inflammatory enzymes and cytokines.

Hemolytic uremic syndrome associated with Shiga toxin producing Escherichia coli infection in a healthy adult woman.

A 49-year-old healthy Japanese woman presented with hemorrhagic diarrhea because of Shiga toxin producing Escherichia coli infection, and then hemolytic uremic syndrome (HUS) developed in the patient. She was successfully treated with continuous hemodiafiltration, plasma exchange, and endotoxin adsorption therapy. An analysis of previous case reports suggests that females aged between 16 and 65 years are at an increased risk of HUS resulting from hemorrhagic colitis. We propose that adult female patients with hemorrhagic colitis should be carefully monitored regardless of their medical history, physical presentation, or laboratory data.

Shiga toxin-producing Escherichia coli as a possible etiological agent of chronic diarrhea.

We identified Shiga toxin-producing Escherichia coli (STEC) as the likely etiologic pathogen for chronic diarrhea in 2 patients, 1 of whom was immunocompromised with acquired immunodeficiency syndrome, and 1 of whom was immunocompetent. Both were treated with antibiotics, and neither developed systemic complications of the infection. These cases suggest that STEC infection should be considered in the differential diagnosis of chronic diarrhea.

Cluster of hemolytic-uremic syndrome caused by Shiga toxin-producing Escherichia coli O26:H11.

BACKGROUND: The epidemiology and clinical characteristics of the hemolytic-uremic syndrome (HUS) caused by Escherichia coli O157:H7 are well-known, but HUS attributable to non-O157:H7 Shiga toxin (Stx)-producing E. coli (STEC) are less thoroughly described. Here we report a cluster of HUS cases caused by STEC O26:H11 the most common non-O157:H7 STEC isolated from sporadic cases of HUS in Europe. METHODS: Three children between 13 and 17 months of age, living in the same small town, developed HUS within an interval of 5 days. We present clinical and microbiologic data on the patients and their infecting isolates. RESULTS: The clinical course ranged from mild uncomplicated HUS to severe HUS complicated by multiorgan involvement. Microbiologic investigation demonstrated STEC of serotype O26:H11 in stools of all the patients. The phenotypic and molecular characterization of the STEC O26:H11 isolates demonstrated that these strains were identical and, unusual for STEC O26, they harbored the stx2 but not the stx1 gene. None of the patients had evidence of STEC O157:H7 infection either by culture or by E. coli O157 serology. The source of the STEC O26:H11 infection was undetermined. CONCLUSIONS: Our results demonstrate that diagnostic procedures based on the detection of stx genes and/or Stx production and subsequent subtyping of the isolates using molecular methods are necessary to identify such outbreaks caused by non-O157:H7 STEC.

Shiga toxin-producing Escherichia coli in children with diarrhea: a prospective point-of-care study.

OBJECTIVE: To conduct a prospective cohort study to determine the frequency and characteristics of Shiga toxin (Stx)-producing Escherichia coli (STEC) infections in children with diarrhea attending an emergency department and a private clinic in Seattle, Washington. METHODS: Between November 1998 and October 2001, 1851 stools were processed for STEC by sorbitol-MacConkey (SMAC) agar screening and a commercial Stx enzyme immunoassay (EIA). RESULTS: STEC belonging to serotypes O157:H7 (n = 28), O103:H2 (n = 4), O118:H16 (n = 2), O26:H11, O111:nonmotile, O111:H8, O121:H19, and O rough:H11 (n = 1 each) were recovered from 39 (2.1%) stools. EIA and SMAC agar detected 89% and 100% of the patients with E coli O157:H7, respectively. E coli O157:H7-infected patients had significantly higher frequencies of bloody stools, fecal leukocytes, and abdominal tenderness and shorter symptom duration. Hemolytic uremic syndrome developed in 5 (18%) and none of the children infected with E coli O157:H7 and non-O157:H7 STEC, respectively (P =.30). CONCLUSIONS: E coli O157:H7 is the predominant STEC in this population. Children infected with E coli O157:H7 have clinical presentations different from those whose stools contain non-O157:H7 STEC. Culture and Stx detection are needed to optimally detect STEC of all serotypes in stools. SMAC agar screening should not be replaced by EIA.