Epidemiology of Shiga Toxin-Producing Escherichia coli Infections in Southern...

[Full title: Epidemiology of Shiga Toxin-Producing Escherichia coli Infections in Southern Italy after Implementation of Symptom-Based Surveillance of Bloody Diarrhea in the Pediatric Population]

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International Journal of Environmental Research and Public Health Article Epidemiology of Shiga Toxin-Producing Escherichia coli Infections in Southern Italy after Implementation of Symptom-Based Surveillance of Bloody Diarrhea in the Pediatric Population Daniela Loconsole 1 , Mario Giordano 2 , Francesca Centrone 1 , Marisa Accogli 1 , Daniele Casulli 1 , Anna Lisa De Robertis 1 , Anna Morea 1 , Michele Quarto 1 , Antonio Parisi 3 , Gaia Scavia 4 , Maria Chironna 1, * and on behalf of the Bloody Diarrhea Apulia Working Group † 1 Department of Biomedical Sciences and Human Oncology-Hygiene Section, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy; daniela.loconsole@uniba.it (D.L.); francesca.centrone.fc@gmail.com (F.C.); marisa.accogli@uniba.it (M.A.); daniele.casulli@hotmail.com (D.C.); derobertis.annalisa@gmail.com (A.L.D.R.); anna.morea@yahoo.com (A.M.); michele.quarto@uniba.it (M.Q.) 2 Pediatric Nephrology and Dialysis Unit, Pediatric Hospital “Giovanni XXIII”, Via Giovanni Amendola, 207, 70126 Bari, Italy; mario.giordano@policlinico.ba.it 3 Istituto Zooprofilattico Sperimentale della Puglia e della Basilicata, Via Manfredonia, 20, 71121 Foggia, Italy; antonio.parisi@izspb.it 4 Food Safety, Nutrition and Veterinary Public Health Department, Istituto Superiore di Sanit à , Viale Regina Elena, 299, 00161 Rome, Italy; gaia.scavia@iss.it * Correspondence: maria.chironna@uniba.it; Tel.: + 39-080-5478498; Fax: + 39-080-5593887 † Bloody Diarrhea Apulia Working Group are listed in acknowledgments Received: 13 June 2020; Accepted: 14 July 2020; Published: 16 July 2020 Abstract: Shiga toxin-producing Escherichia coli (STEC) infections result in a significant public health impact because of the severity of the disease that, in young children especially, can lead to hemolytic–uremic syndrome (HUS). A rise in the number of HUS cases was observed in the Apulia region of Italy from 2013 to 2017, and so, in 2018, a symptom-based surveillance system for children with bloody diarrhea (BD) was initiated in order to detect and manage STEC infections. The objective of the study was to describe the epidemiology of STEC infections in children from June 2018 to August 2019. Children < 15 years old with BD were hospitalized and tested for STEC. Real-time PCR for virulence genes ( stx 1 , stx 2 , eae ) and serogroup identification tests were performed on stool samples / rectal swabs of cases. STEC infection was detected in 87 (10.6%) BD cases. The median age of STEC cases was 2.7 years, and 60 (68.9%) were < 4. Of these 87 cases, 12 (13.8%) came from households with diarrhea. The reporting rate was 14.2 / 100,000, with the highest incidence in cases from the province of Bari (24.2 / 100,000). Serogroups O 26 and O 111 were both detected in 22 / 87 (25.3%) cases. Co-infections occurred in 12.6% of cases (11 / 87). Twenty-nine STEC were positive for stx 1 , stx 2 , and eae . Five cases (5.7%) caused by O 26 (n = 2), O 111 (n = 2), and O 45 (n = 1) developed into HUS A risk-oriented approach based on the testing of children with BD during the summer may represent a potentially beneficial option to improve the sensitivity of STEC surveillance, not only in Italy but also in the context of Europe as a whole Keywords: epidemiology; surveillance; Shiga toxin-producing Escherichia coli ; bloody diarrhea; hemolytic–uremic syndrome; Italy Int. J. Environ. Res. Public Health 2020 , 17 , 5137; doi:10.3390 / ijerph 17145137 www.mdpi.com / journal / ijerph

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Int. J. Environ. Res. Public Health 2020 , 17 , 5137 2 of 12 1. Introduction Shiga toxin-producing Escherichia coli (STEC) infections in humans are responsible for causing severe gastrointestinal symptoms, including watery diarrhea and hemorrhagic colitis, and they may also potentially progress to produce severe systemic disorders. STEC infections represent a worldwide public health issue, and the World Health Organization (WHO) estimated that, in 2010, foodborne STEC infections amounted to more than one million cases and 100 deaths globally [ 1 ]. In 10–15% of patients, STEC infections may result in hemolytic–uremic syndrome (HUS), which is characterized by microangiopathic hemolysis, platelet destruction, and renal failure [ 2 , 3 ]. This condition is mainly triggered by the e ff ects of the Shiga toxin released by STEC in the endothelial cells of target organs, mainly the kidneys. HUS a ff ects children in particular, with a peak of incidence in children < 5 years of age, and it shows a case-fatality rate ranging from 3% to 5% [ 4 ]. It is the most common cause of acute renal failure in young children and leads to neurological involvement in 25% of cases [ 3 ]. Inducing early volume expansion after the occurrence of typical prodromal symptoms of STEC infection represent an opportunity to reduce organ damage in patients at risk of developing HUS, because hemoconcentration and dehydration are considered risk factors for the evolution of HUS [ 5 – 7 ]. Transmission pathways of STEC infection include the fecal–oral, foodborne, environmental, and person-to-person routes [ 8 ]. The latter, in particular, occurs especially in childcare facilities [ 9 ]. Serotype O 157:H 7 STEC is considered to be most commonly associated with incidents of disease [ 10 – 12 ] and to cause severe infections [ 2 ]. Nonetheless, as reported for many countries, non-O 157 STEC serogroups also have the same pathogenic potential [ 13 ]. HUS is frequently associated with STEC strains carrying the stx 2 and eae genes, and this gene composition is considered high risk for the development of HUS [ 11 , 14 ]. In recent years, outbreaks caused by non-O 157 STEC infections with this pattern of virulence genes have been reported in Europe [ 15 – 18 ]. STEC infections are mandatorily notifiable in most EU / EEA (European Economic Area) countries, with the exception of five (France, Luxemburg, Spain, Italy, and the United Kingdom), and surveillance systems have national coverage in all countries except for France, Italy, and Spain [ 19 ]. Furthermore, most EU / EAA countries have a passive surveillance system, and only five have laboratory-based reporting of STEC infections In Italy, the STEC surveillance system is primarily based on pediatric HUS cases [ 19 ] and, consequently, the occurrence of STEC infection is underestimated [ 18 , 20 ]. During the 1988–2018 surveillance period, HUS cases steadily increased, and non-O 157 STEC infections, in particular O 26, emerged as the most prevalent serogroups [ 21 ]. In the Apulia region (Southern Italy), the mean annual reporting rate of HUS in the pediatric population (0.67 HUS cases / 100,000 population) was among the highest rates observed in Italy, and the number of HUS cases reported between 2008 and 2017 was 4.6 times higher than in the previous decade (Scavia, personal communication, 2019). This rise was caused by both a severe outbreak of STEC O 26 infections in 2013 that caused 20 cases of HUS in children, with many of them developing long-lasting sequelae [ 18 ], and higher than expected numbers of sporadic HUS cases occurring between January 2017 and June 2018 (data from Regional Epidemiological Observatory and National Registry of HUS) Three deaths resulting from HUS and its complications caused by STEC infections occurred in the same period. The deaths of these very young children ( < 2 years) had a dramatic impact on the local media. The recent increase in the number of HUS cases in Apulia has made it necessary to implement strategies to improve the prevention and control of STEC infections and HUS. The implementation of symptom-based surveillance of bloody diarrhea (BD) in the pediatric population was therefore established in 2018 through an operating protocol [ 22 ]. The purpose of the surveillance was to both improve the sensitivity of STEC monitoring in the pediatric population, in order to allow the early identification of patients at risk of developing HUS and to detect STEC outbreaks, and to contribute to the characterization of the epidemiology of STEC

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Int. J. Environ. Res. Public Health 2020 , 17 , 5137 3 of 12 infections in children. In this study, we report the results of the surveillance of STEC infections causing bloody diarrhea (BD) in children in Apulia from June 2018 to August 2019 2. Materials and Methods 2.1. Surveillance Setting Apulia is a populous region of Southern Italy, with more than four million inhabitants, of whom 527,894 are children < 15 years old (Source demographic data: ISTAT, 2019; http: // demo.istat.it / pop 2018 / index.html ). In the region, there are 24 hospitals with pediatric units: seven in the province of Bari, three in the province of Barletta-Andria-Trani (BT), two in the province of Brindisi, four in the province of Foggia, five in the province of Lecce, and three in the province of Taranto 2.2. Epidemiological Surveillance and Operating Protocol for Management of Bloody Diarrhea A STEC infection symptom-based surveillance system for the pediatric population was established in Apulia in June 2018. The population under surveillance included children < 15 years presenting with BD, which was defined as any amount of blood in the loose stool when examined or reported by parents during the previous 2 weeks [ 22 ]. According to the protocol, all pediatric units in regional hospitals had to admit all children presenting with BD, conduct a prompt diagnosis of STEC infection, and prevent complications, as suggested in previous studies [ 5 – 7 ]. Patients with BD who were identified by primary care pediatricians or by public pediatric outpatient services were immediately hospitalized in the nearest hospital with a pediatric unit. Stool samples / rectal swabs were collected promptly after hospitalization and submitted to the laboratory for STEC testing. In addition, both blood count and renal functions were assessed according to the operating protocol [ 22 ]. Personal data and information on the clinical course of the illness and treatment, including antimicrobials administered before hospitalization, were collected for each case Examination of biological specimens for STEC was centralized at the Regional Reference Laboratory of Molecular Epidemiology and Public Health of the Hygiene Unit of the Azienda Ospedaliero-Universitaria Policlinico University Hospital of Bari. Where a STEC infection was identified, the patient’s household contacts were invited, on a voluntary basis, to submit stool samples for STEC testing, even in the absence of symptoms 2.3. Laboratory Diagnosis of STEC Infections Stool samples and rectal swabs underwent molecular detection of STEC. Total nucleic acid was extracted using the MagnaPure LC automated extraction system (Roche Diagnostics, Milan, Italy) A commercial multiplex real-time PCR kit (FTD, Bacterial gastroenteritis, FastTrack Diagnostics, Luxembourg) was then used for the detection of the stx 1 / 2 genes. The results of the laboratory test were communicated to the pediatric hospitals within 24 hours of the arrival of fecal samples Samples that were positive for the presence of STEC were subsequently tested for the presence of the stx 1 , stx 2 , and eae virulence genes by a real-time PCR test (PATHfinder E. coli VTEC stx 1-stx 2 & eae -IAC Duplex Assay, Generon, San Prospero, Modena, Italy). When the molecular test for the virulence genes yielded a negative result, the multiplex real-time PCR for the detection of stx 1 / 2 genes was repeated, and if the presence of stx 1 / 2 genes was confirmed (cycle threshold < 38), the sample was classified as positive for STEC. Serogroup identification was performed on samples by a commercial real-time PCR test that identifies serogroups O 26, O 45, O 103, O 104, O 111, O 121, O 145, and O 157 (STEC Identification LyoKit, BIOTECON Diagnostics GmbH, Potsdam, Germany) 2.4. Data Analysis Data analysis was performed on the demographic and clinical information collected through the surveillance form. Continuous data are reported as medians with the interquartile range (IQR).

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Int. J. Environ. Res. Public Health 2020 , 17 , 5137 4 of 12 Analysis of data was performed with STATA 12.0 software (StataCorp LLC, College Station, TX 77845-4512, USA) 2.5. Ethical Statement The study was not submitted for approval by a research ethics committee because the activities described were conducted as part of the legislated mandate of the Health Promotion and Public Health Department of Apulia, the competent authority for the surveillance of communicable diseases according to Nota Prot. AOO_005_000221 of 21 June 2018, which created the epidemiological surveillance network for BD in Apulia. All activities undertaken formed part of public health surveillance and did not require informed consent. Informed written consent was obtained from all household contacts, or the legal guardians of contacts, of STEC cases who provided samples for STEC detection 3. Results Between 22 nd June 2018 and 21 st August 2019, 823 cases of BD in children were identified. Of these, 781 (94.9%) were residents and 42 (5.1%) were non-residents of Apulia. Of the total cases, 55.5% (n = 457) were male and 44.5% (n = 366) female. The median age of resident cases was 3.3 years (IQR: 1.5–7.0) The reporting rate of BD in the resident population was 147.9 per 100,000 children < 15 years old A STEC infection was detected in 87 (10.6%) of the BD cases. A clear seasonality in the distribution of STEC infections by month was observed during the surveillance period (Figure 1 ), with STEC positive cases peaking in the summer Int. J. Environ. Res. Public Health 2020 , 17 , x 4 of 12 Health Department of Apulia, the competent authority for the surveillance of communicable diseases according to Nota Prot. AOO_005_000221 of 21 June 2018, which created the epidemiological surveillance network for BD in Apulia. All activities undertaken formed part of public health surveillance and did not require informed consent. Informed written consent was obtained from all household contacts, or the legal guardians of contacts, of STEC cases who provided samples for STEC detection. 3. Results Between 22 nd June 2018 and 21 st August 2019, 823 cases of BD in children were identified. Of these, 781 (94.9%) were residents and 42 (5.1%) were non-residents of Apulia. Of the total cases, 55.5% (n = 457) were male and 44.5% (n = 366) female. The median age of resident cases was 3.3 years (IQR: 1.5–7.0). The reporting rate of BD in the resident population was 147.9 per 100,000 children <15 years old. A STEC infection was detected in 87 (10.6%) of the BD cases. A clear seasonality in the distribution of STEC infections by month was observed during the surveillance period (Figure 1), with STEC positive cases peaking in the summer. Figure 1. Distribution of confirmed cases of Shiga toxin-producing Escherichia coli (STEC) infection in children (<15 years old) by month, Apulia region, June 2018–August 2019. The geographical distribution of cases also showed differences, with the greatest number of STEC positive cases occurring in the province of Bari (n = 40; 46% of all STEC positive cases). Altogether, STEC positive cases from all the other Apulia provinces (Lecce, n = 15; Foggia, n = 12; BT, n = 8; Brindisi, n = 7; Taranto, n = 5) accounted for 47/87 STEC cases (54%). Of the STEC cases, 50.6% (44/87) were females, and the median age was 2.7 years (IQR: 1.6–5.9). Sixty cases were in children from 0 to 4 years old (68.9%) and six in infants <1 year old. Fever was reported in 34.5% of cases (n = 30) and vomiting in 25.3% (n = 22). Households with diarrhea were associated with 13.8% of cases (n = 12). Antibiotic use was reported in 10/87 cases (11.5%). The mean annual reporting rate of cases with STEC infection estimated for the whole surveillance period was 14.2/100,000 in children <15 years old in the Apulia region, with the highest value obtained for the province of Bari (20.6/100,000) (Figure 2). In Apulia, the incidence for children aged 0–1 years was 42.5/100,000, and for those who were 2–4 years old, it was 28.3/100,000 (Figure 3). Figure 1. Distribution of confirmed cases of Shiga toxin-producing Escherichia coli (STEC) infection in children ( < 15 years old) by month, Apulia region, June 2018–August 2019 The geographical distribution of cases also showed di ff erences, with the greatest number of STEC positive cases occurring in the province of Bari (n = 40; 46% of all STEC positive cases). Altogether, STEC positive cases from all the other Apulia provinces (Lecce, n = 15; Foggia, n = 12; BT, n = 8; Brindisi, n = 7; Taranto, n = 5) accounted for 47 / 87 STEC cases (54%). Of the STEC cases, 50.6% (44 / 87) were females, and the median age was 2.7 years (IQR: 1.6–5.9). Sixty cases were in children from 0 to 4 years old (68.9%) and six in infants < 1 year old. Fever was reported in 34.5% of cases (n = 30) and vomiting in 25.3% (n = 22). Households with diarrhea were associated with 13.8% of cases (n = 12) Antibiotic use was reported in 10 / 87 cases (11.5%) The mean annual reporting rate of cases with STEC infection estimated for the whole surveillance period was 14.2 / 100,000 in children < 15 years old in the Apulia region, with the highest value obtained for the province of Bari (20.6 / 100,000) (Figure 2 ). In Apulia, the incidence for children aged 0–1 years was 42.5 / 100,000, and for those who were 2–4 years old, it was 28.3 / 100,000 (Figure 3 ).

Int. J. Environ. Res. Public Health 2020 , 17 , 5137 5 of 12 Int. J. Environ. Res. Public Health 2020 , 17 , x 5 of 12 Figure 2. Mean annual reporting rate (per 100,000 children <15 years old) of cases of STEC infection by province, Apulia region. Figure 3. Mean annual reporting rate (per 100,000 children <15 years old) of cases of STEC infection by age group, Apulia region. Among all serogroups identified (n = 98), comprising co-infections, the most prevalent serogroups were O 26 and O 111 (both n = 24, 25.5%), followed by O 157 (n = 19, 19.4%) and O 145 (n = 9, 9.2%) (Figure 4). For 11 children, infection with STEC belonging to two serogroups was identified (O 111/O 103, O 111/O 145, O 111/O 45, O 145/O 45, O 157/O 104, O 157/O 145, O 26/O 157, and O 26/O 45 in one case each and O 26/O 111 in three cases). Figure 2. Mean annual reporting rate (per 100,000 children < 15 years old) of cases of STEC infection by province, Apulia region Int. J. Environ. Res. Public Health 2020 , 17 , x 5 of 12 Figure 2. Mean annual reporting rate (per 100,000 children <15 years old) of cases of STEC infection by province, Apulia region. Figure 3. Mean annual reporting rate (per 100,000 children <15 years old) of cases of STEC infection by age group, Apulia region. Among all serogroups identified (n = 98), comprising co-infections, the most prevalent serogroups were O 26 and O 111 (both n = 24, 25.5%), followed by O 157 (n = 19, 19.4%) and O 145 (n = 9, 9.2%) (Figure 4). For 11 children, infection with STEC belonging to two serogroups was identified (O 111/O 103, O 111/O 145, O 111/O 45, O 145/O 45, O 157/O 104, O 157/O 145, O 26/O 157, and O 26/O 45 in one case each and O 26/O 111 in three cases). Figure 3. Mean annual reporting rate (per 100,000 children < 15 years old) of cases of STEC infection by age group, Apulia region Among all serogroups identified (n = 98), comprising co-infections, the most prevalent serogroups were O 26 and O 111 (both n = 24, 25.5%), followed by O 157 (n = 19, 19.4%) and O 145 (n = 9, 9.2%) (Figure 4 ). For 11 children, infection with STEC belonging to two serogroups was identified (O 111 / O 103, O 111 / O 145, O 111 / O 45, O 145 / O 45, O 157 / O 104, O 157 / O 145, O 26 / O 157, and O 26 / O 45 in one case each and O 26 / O 111 in three cases).

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Int. J. Environ. Res. Public Health 2020 , 17 , 5137 6 of 12 Int. J. Environ. Res. Public Health 2020 , 17 , x 6 of 12 Figure 4. Distribution of STEC serogroups (n = 98) detected in children with bloody diarrhea, Apulia region, June 2018–August 2019. Although positive by the molecular screening test for stx 1/stx 2, 11/87 samples produced a negative result in the molecular test used to discriminate the stx 1 and stx 2 genes. These discrepancies in results could be explained by a different sensitivity in the target detection of the molecular methods used. In Table 1, the distribution of serogroup and virulence gene composition for samples from 76 cases of STEC infection is reported. The presence of stx 1 + stx 2 was found in samples from 31/76 cases (40.8%). All three main virulence genes ( stx 1 , stx 2 , eae ) were detected in 29 cases (38.2%), mainly in samples that tested positive for serogroups O 111 and O 157. Table 1. Distribution of cases of STEC infection with identified virulence pattern (n = 76) by STEC serogroup and virulence genes, Apulia region, July 2018–August 2019. Virulence Genes No. of Cases Serogroup stx 1 stx 2 stx 1+stx 2 eae 18 O 26 n = 1 - - + + n = 14 + - - + n = 2 - + - + n = 1 - + - - 17 O 111 n = 14 - - + + n = 2 - + - + n = 1 - + - - 15 O 157 n = 11 - - + + n = 4 - + - + 6 O 145 n = 2 - - + + n = 2 + - - + n = 2 - + - + Figure 4. Distribution of STEC serogroups (n = 98) detected in children with bloody diarrhea, Apulia region, June 2018–August 2019 Although positive by the molecular screening test for stx 1 / stx 2 , 11 / 87 samples produced a negative result in the molecular test used to discriminate the stx 1 and stx 2 genes. These discrepancies in results could be explained by a di ff erent sensitivity in the target detection of the molecular methods used In Table 1 , the distribution of serogroup and virulence gene composition for samples from 76 cases of STEC infection is reported. The presence of stx 1 + stx 2 was found in samples from 31 / 76 cases (40.8%) All three main virulence genes ( stx 1 , stx 2 , eae ) were detected in 29 cases (38.2%), mainly in samples that tested positive for serogroups O 111 and O 157 In the whole period of surveillance, five children (5.7%) with STEC infections developed HUS In addition, six cases not detected by surveillance occurred (one of these cases was resident outside of the region). The mean annual reporting rate of HUS cases (n = 11) in the period considered was 1.8 / 100,000. In 2018, two STEC-associated HUS cases occurred in female twins of 18 months of age, and these were caused by STEC O 26; one case in a 7-year-old female was caused by STEC O 45; and one case in a 9-year-old female was caused by STEC O 111. The only case that occurred in 2019 was in a 2-year-old female and was caused by STEC O 111. All STEC-associated HUS cases were positive for the virulence genes stx 1 , stx 2 , and eae In 18 / 87 (20.7%) cases of STEC infection, samples from household contacts were collected Investigation of STEC cases’ family contacts allowed the identification of ten further STEC infections (one with diarrhea and nine asymptomatic), linked to seven STEC-positive children with BD. All ten positive household contacts were older than the cases. Five contacts were adults and five were siblings. Samples from all but one STEC-positive household showed the same serogroup and virulence genes as the cases Starting from the activation of the surveillance, it seems that no outbreaks of HUS occurred.

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Int. J. Environ. Res. Public Health 2020 , 17 , 5137 7 of 12 Table 1. Distribution of cases of STEC infection with identified virulence pattern (n = 76) by STEC serogroup and virulence genes, Apulia region, July 2018–August 2019 Virulence Genes No. of Cases Serogroup stx 1 stx 2 stx 1 + stx 2 eae 18 O 26 n = 1 - - + + n = 14 + - - + n = 2 - + - + n = 1 - + - - 17 O 111 n = 14 - - + + n = 2 - + - + n = 1 - + - - 15 O 157 n = 11 - - + + n = 4 - + - + 6 O 145 n = 2 - - + + n = 2 + - - + n = 2 - + - + 1 O 103 n = 1 + - - + 9 Co-Infections O 111 / O 26 n = 2 + - - + O 111 / O 45 n = 1 - - + + O 111 / O 103 n = 1 - + - + O 145 / O 45 n = 1 - + - + O 157 / O 104 n = 1 - + - + O 157 / O 145 n = 1 - + - + O 26 / O 157 n = 1 - + - + O 111 / O 145 n = 1 - - + - 10 Other Serogroups n = 1 + - - + n = 5 - + - + n = 1 - - + - n = 3 - + - - 4. Discussion This study describes the epidemiology of STEC infections in children with BD in Southern Italy after the implementation of a symptom-based surveillance program. During the study, the reporting rates for STEC infections and HUS cases in the pediatric population were 14.2 and 1.8 cases / 100,000, respectively, amounting to a ratio of almost eight children with BD and STEC infection for every single case of pediatric HUS Compared with the mean notification rate of STEC infections in the EU / EEA in 2018 of 2.3 cases / 100,000 population [ 23 ], the reporting rate of STEC infection estimated in our study is more than six times higher. It is only exceeded by Ireland (20.0 cases / 100,000), which is the EU country

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Int. J. Environ. Res. Public Health 2020 , 17 , 5137 8 of 12 with the highest notification rate over the last 5 years. Besides true epidemiological di ff erences, the higher reporting rate estimated in Apulia is, we suggest, attributable to the active testing of symptomatic cases presenting with BD, although other reasons may also contribute to this finding. Our study only focused on pediatric cases ( < 15 years old), which is the population at the highest risk for STEC infection. In addition, the period of surveillance in Apulia mainly included the warmer seasons, when STEC infections are at their highest. While these factors may introduce a bias in the comparability of our findings with the estimates at the EU / EEA level, which are for the whole population and are not seasonally biased, the results of this study can be interpreted as reflecting results obtained by improving the sensitivity of a surveillance program. Our results suggest that a risk-oriented approach, based on the active testing of children with BD, especially during the risk season, may be a potentially beneficial option for improving the sensitivity of STEC surveillance During the surveillance period, STEC infection was identified in approximately 11% of BD cases This finding is consistent with 9% being reported in a one-year cohort study conducted recently in a single hospital, where 108 cases of BD were studied [ 24 ]. Most cases of STEC infection, irrespective of serogroup, occurred in the warmer months, thus agreeing with other studies that also found a seasonal trend for STEC infections [ 19 , 25 ]. The province of Bari showed the highest reporting rate of STEC infections during the surveillance period. This finding could reflect the real incidence of STEC infections in this province or an under-notification of BD cases by hospitals in other provinces in the first few months of the surveillance, as well as the failure to send fecal samples for testing because of the distance from the Regional Reference Laboratory. Notably, HUS cases detected in recent years in Apulia were mainly reported in the province of Bari. Furthermore, the majority of HUS cases occurred during a 2013 outbreak that occurred in the same province [ 18 ]. It could be hypothesized that the population of this province is more frequently exposed to risk factors for STEC infections, such as a wider environmental circulation of the pathogen or a higher frequency of consumption of contaminated food Data produced in the present study show that 70% of STEC positive cases in the pediatric population occurred in the 0–4 years age group. In the EU, almost one-third of all confirmed STEC cases have been reported in children aged < 4 years, which is the age group with the highest reporting rate (8.9 cases / 100,000 population), confirming that very young children are at a higher risk of infection than people of other ages [ 19 , 26 , 27 ]. In the EU, O 157 is the most frequently detected serogroup, but in recent years, the emergence of non-O 157 serogroups has been reported [ 19 ]. This is possibly an e ff ect of the increasing awareness of non-O 157 STEC, as well as the fact that more laboratories commenced testing for serogroups other than O 157 [ 28 ]. Overall, non-O 157 STEC infections accounted for more than 80% of the total, and serogroups O 26 and O 111 were the most frequently occurring serogroups in Apulia. In Italy, the most common non-O 157 serogroups that were reported were also O 26 and O 111 (National Registry of HUS). In addition, these findings agree with the estimated proportion of non-O 157 STEC infections in Germany, which accounted for approximately 80% of all gastroenteritis cases caused by STEC and half of all BD caused by STEC [ 29 ]. Even in countries outside Europe, non-O 157 serogroups are becoming more commonly detected than serogroup O 157. For example, in Canada, the estimated proportion of non-O 157 serogroups causing gastroenteritis was 62% [ 30 ], while in the United States, it was 64% [ 31 ]. Shiga toxins produced by the stx 1 and stx 2 genes are the main virulence factors of STEC [ 32 ], whereas the eae gene, encoding for intimin protein, mediates the attachment of STEC to the enterocytes [ 33 ]. It is known that stx 2 and eae genes, along with young age, play the roles of risk factors for the development of HUS [ 11 , 14 , 27 ]. In our study, samples from 32.9% (25 / 76) of STEC cases harbored the stx 2 gene (single and co-infection). It has been suggested that infections caused by E.coli strains carrying the stx 2 gene are more likely to result in HUS than those caused by STEC carrying both stx 1 and stx 2 , thus indicating that stx 1 could mitigate, to some extent, the e ff ect of the stx 2 gene [ 14 ]. However, the five HUS cases observed in Apulia during the surveillance period, who were

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Int. J. Environ. Res. Public Health 2020 , 17 , 5137 9 of 12 previously diagnosed with a STEC infection, as well as 3 / 6 further HUS cases registered in the region, were all caused by STEC that were positive for the stx 1 , stx 2 and eae genes. This di ff erence could be related to the fact that, in the previous study, approximately 50% of STEC infections were caused by serogroup O 157 and were found in all age groups, whereas our surveillance targeted only the pediatric population, and non-O 157 STEC were the prevalent serogroups involved with infections During the surveillance period, < 6% of cases detected and diagnosed as STEC-positive developed HUS, which is lower than the 15% reported by Tarr et al. and 20% by Adams N et al., although the latter data relate to STEC O 157 infections only [ 2 , 27 ]. Not all the patients with STEC infection develop BD, and this finding may partly explain this di ff erence. Moreover, very few data are available regarding the development into HUS of non-O 157 STEC infections or, in particular, regarding the emerging O 26 and O 111 STEC serogroups, which represented more than 50% of the STEC infections in the present study. In the 2011 community-wide outbreak caused by STEC O 104 in Germany, HUS occurred in 22% of cases [ 16 ], thus indicating that non-O 157 STEC infections could more frequently lead to complications However, the outbreak strain was considered to be a hybrid possessing an unusual combination of pathogenic features typical of enteroaggregative E. coli , together with the capacity to produce the Shiga toxin The risk of developing HUS could be associated with genetic factors [ 34 ]. This aspect could be hypothesized in the two female twins with STEC O 26 infection but, unfortunately, this issue was not investigated STEC are zoonotic agents, and human infections are mostly related to foodborne exposure, but person-to-person spread is also common due to the possibility for infections to occur even at low doses [ 35 , 36 ]. In our study, ten STEC infections were identified in the household contacts of STEC cases, probably indicating an exposure to the same source of infection or person-to-person transmission. The latter transmission route is common in childcare settings [ 13 , 37 ]. Further investigations into the carriage by, or infection of, household contacts are needed in order to allow a better evaluation of the role of person-to-person transmission within family settings and to elucidate further the sources of infection in young children and infants This study contributes to an improved understanding of the epidemiological framework of STEC infections in Southern Italy, but it has some limitations. Firstly, the implementation of the surveillance program during the startup phase in the summer of 2018 could have been a ff ected by a lack of dissemination of the protocol among pediatricians. Secondly, pediatric units of more distant provinces from the Regional Reference Center for STEC diagnosis and surveillance may not have sent fecal samples from all hospitalized children with BD, and this could explain di ff erences in the reporting rates in some provinces of the region. Thirdly, no statistical analysis was performed in the study to compare data or to assess local risk factors that can influence the probability of STEC infection among BD patients. Taken together, these factors may have a ff ected the e ffi ciency of STEC infection detection Nonetheless, the surveillance established in Apulia can be considered as a pilot project and provides preliminary experience in exploring ways to obtain robust data on this emerging public health problem The increasing number of HUS cases in Apulia over recent years presents a concern about the negative impact on regional productivity, as Apulia is a leading region for dairy products, a food commodity thought to be involved in the 2013 outbreak [ 18 ]. STEC infections are often travel-related, with many children developing HUS after returning from typical tourist destinations. Therefore, this experience is also relevant in view of the importance of the region as a tourist destination. Our symptom-based surveillance of BD in children could represent a valid model for enhancing STEC surveillance at a national level, even for limited time periods (e.g., peak STEC season) The implementation of a nationwide surveillance program and the application of strict preventive measures could help to reduce the impact of STEC infections.

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Int. J. Environ. Res. Public Health 2020 , 17 , 5137 10 of 12 5. Conclusions Continuation of the current surveillance of BD in children and the application of the operating protocol established in Apulia will help to clarify many cryptic aspects of STEC infection, such as the burden of the disease. Additionally, the molecular characterization of STEC strains could provide valuable further information, particularly in outbreak investigations. Finally, more e ff ective preventive measures should be enforced in order to control STEC carriage in animals and its spread to the environment [ 31 ], since a one-health approach is needed in order to reduce the occurrence of outbreaks Author Contributions: Conceptualization, D.L. and M.C.; Data curation, M.G. and F.C.; Formal analysis, F.C.; Investigation, M.A., D.C., A.L.D.R., A.M., M.Q., and Bloody Diarrhea Working Group; Methodology, M.G., M.Q., A.P. and G.S.; Writing—original draft, D.L., G.S. and M.C.; Writing—review and editing, A.P. and M.C. All authors have read and agreed to the published version of the manuscript Funding: This research received no external funding Acknowledgments: Bloody Diarrhea Apulia Working Group: Onofrio Mongelli, Diletta Torres, Luisa Santangelo, Vincenza Carbone, Giovanni Piscopo, Domenico Larovere, Desir é e Caselli, Angelo Campanozzi, Mariano Manzionna, Giovanni Ciccarone, Maria Giovanna Mirizzi, Leonardo Di Terlizzi, Ignazio Lof ù , Baldassarre Martire, Angelo Acquafredda, Biagio De Mitri, Domenico Paternostro, Valerio Cecinati, Fulvio Moramarco, Pasquale Padalini, Vincenzo Forziati, Michele Sacco, Matteo Mariano, Ra ff aele Montinaro, Carmelo Perrone, Franco Mastro, Paola Giordano, Nicola Laforgia, Alessandro Tronci Conflicts of Interest: The authors declare no conflict of interest References 1 Havelaar, A.H.; Kirk, M.D.; Torgerson, P.R.; Gibb, H.J.; Hald, T.; Lake, R.J.; Praet, N.; Bellinger, D.C.; De Silva, N.R.; Gargouri, N.; et al. World Health Organization global estimates and regional comparisons of the burden of foodborne disease in 2010 PLoS Med 2015 , 12 , e 1001923. [ CrossRef ] [ PubMed ] 2 Tarr, P.I.; Gordon, C.A.; Chandler, W.L. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome Lancet 2005 , 365 , 1073–1078. [ CrossRef ] 3 World Health Organization (WHO) E. coli Key Facts (7 February 2018). Available online: https: // www.who. int / news-room / fact-sheets / detail / e-coli (accessed on 12 April 2019) 4 Fitzpatrick, M. Haemolytic uraemic syndrome and E. coli O 157 Br. Med. J 1999 , 318 , 684–685. [ CrossRef ] [ PubMed ] 5 Ake, J.A.; Jelacic, S.; Ciol, M.A.; Watkins, S.L.; Murray, K.F.; Christie, D.L.; Klein, E.J.; Tarr, P.I. Relative nephroprotection during Escherichia coli O 157:H 7 infections: Association with intravenous volume expansion Pediatrics 2005 , 115 , e 673–e 680. [ CrossRef ] 6 Hickey, C.A.; Beattie, T.J.; Cowieson, J.; Miyashita, Y.; Strife, C.F.; Frem, J.C.; Peterson, J.M.; Butani, L.; Jones, D.P.; Havens, P.L.; et al. Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome Arch. Pediatr. Adolesc. Med 2011 , 165 , 884–889. [ CrossRef ] 7 Ardissino, G.; Tel, F.; Possenti, I.; Testa, S.; Consonni, D.; Paglialonga, F.; Salardi, S.; Borsa-Ghiringhelli, N.; Salice, P.; Tedeschi, S.; et al. Early volume expansion and outcomes of hemolytic uremic syndrome Pediatrics 2016 . [ CrossRef ] 8 Kintz, E.; Brainard, J.; Hooper, L.; Hunter, P. Transmission pathways for sporadic Shiga-toxin producing E. coli infections: A systematic review and meta-analysis Int. J. Hyg. Environ. Health 2017 , 220 , 57–67 [ CrossRef ] 9 Garvey, P.; Carroll, A.; McNamara, E.; McKeown, P.J. Verotoxigenic Escherichia coli transmission in Ireland: A review of notified outbreaks, 2004–2012 Epidemiol. Infect 2016 , 144 , 917–926. [ CrossRef ] 10 Adams, N.L.; Byrne, L.; Smith, G.A.; Elson, R.; Harris, J.P.; Salmon, R.; O’Brien, S.J.; Adak, G.K.; Jenkins, C. Shiga toxin-producing Escherichia coli O 157, England and Wales, 1983–2012 Emerg. Infect. Dis 2016 , 22 , 590–597. [ CrossRef ] [ PubMed ] 11 Brandal, L.T.; Wester, A.L.; Lange, H.; Løbersli, I.; Lindstedt, B.A.; Vold, L.; Kapperud, G. Shiga toxin-producing Escherichia coli infections in Norway, 1992–2012: Characterization of isolates and identification of risk factors for haemolytic uremic syndrome BMC Infect. Dis 2015 , 15 , 324. [ CrossRef ] [ PubMed ]

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Hu, Public health, Preventive measure, Public Health Problem, Pediatric Population, Acute Renal Failure, Escherichia coli, Molecular characterization, Real-time PCR, Informed written consent, Renal failure, Genetic factor, Epidemiology, Pediatric Unit, Risk factor, Public Health Department, Bloody diarrhea, Eae gene, Molecular detection, Co-infection, One Health approach, Person-to-person spread, Reporting Rate, Local risk factors, Shiga toxin, Italy, Notification rate, Transmission pathway, Dairy product, Pilot project, Outbreak investigation, Virulence gene, Shiga toxin-producing Escherichia coli, Surveillance, Foodborne, Southern Italy, Household contact, Stool sample, Surveillance program, Family setting, Department of Biomedical Science, Hemorrhagic colitis, STEC, Zoonotic agent, STEC infection, Watery diarrhea, Northern Italy, Tourist destination, Enteroaggregative E. coli, Rectal swab, Apulia Region.