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Diarrea emorragica acuta, infezione da Escherichia coli produttori di Shiga tossine e sindrome emolitica uremica
Expert inter-society consensus on the management of acute bloody diarrhoea focused on STEC infection and haemolytic uremic syndrome
Documento d’indirizzo inter-societario
Ottobre 2025 - pagg. 510 -518 | DOI: 10.53126/MEB44510
Abstract
Haemolytic uremic syndrome (HUS) associated with Shiga toxin-producing Escherichia coli (STEC) infection is a major individual and public health challenge and is the leading cause of acute kidney injury in children. In Western countries, HUS complicates about 15% of STEC infections, which usually present with acute bloody diarrhoea (ABD). At least 6-7% of cases of ABD in children (rising to 15-20% during summer) are caused by STEC. The widespread use of molecular microbiology techniques enables the diagnosis of STEC infection before HUS onset in an increasing number of patients and generates a window of preventive and/or therapeutic opportunities. Given the rapid progression of the disease, all children with ABD should be tested as early as possible for Shiga toxin (Stx) encoding genes. Stx-positive patients should then be closely monitored for HUS development by urine dipstick for the development of haemoglobinuria. This proactive diagnostic approach allows the application of measures aimed to prevent or mitigate the severity of HUS among which stands the early and generous fluid administration. Moreover, although antibiotics are not recommended in STEC infections, recent data suggest a promising potential preventive role for bacteriostatic agents (e.g. azithromycin), if administered early during the infection. The aim of the present contribution is to share the approach to ABD and STEC infection as endorsed by the scientific societies actively engaged in this area (AMCLI, SIGENP, SIMEUP, SIN, SIP, SIPPS, SITIP). The goal is to promote the early diagnosis of STEC infection by molecular microbiology of ABDs nationwide, thereby improving the understanding of the mechanisms of disease spreading and hopefully reducing the incidence of HUS and its case fatality rate as well as improving both short- and long-term outcomes.
Riassunto
La sindrome emolitica uremica (SEU) secondaria a Escherichia coli Shiga tossino-produttori (STEC) rimane un importante problema clinico, individuale e di sanità pubblica essendo tra le principali cause di insufficienza renale acuta in bambini precedentemente sani. Nei Paesi occidentali la SEU complica circa il 15% delle infezioni da STEC e si presenta abitualmente con una fase prodromica caratterizzata da diarrea acuta con sangue (DEA). Almeno 6-7% delle DEA dei bambini sono causate da STEC e questa percentuale sale fino al 20% durante i mesi di luglio, agosto e settembre. L’impiego sempre più diffuso di tecniche diagnostiche di microbiologiche basate sulla biologia molecolare consente oggi di identificare l’infezione da STEC prima che diventi SEU. Questa anticipazione della diagnosi genera una finestra di potenziali opportunità preventive e/o terapeutiche nei confronti della SEU. In considerazione della gravità e rapidità di progressione della SEU, tutti i pazienti con DEA dovrebbero essere sottoposti, urgentemente, a test per la ricerca dei geni codificanti le Shiga toxin (Stx). I pazienti positivi per Stx dovrebbero essere monitorati attentamente per la possibilità di sviluppo di SEU mediante lo stick urine per emoglobinuria fino a guarigione della diarrea. Questo approccio proactivo alla diagnosi di infezione da STEC in pazienti con DEA, consente di mettere in atto misure potenzialmente utili a prevenire la SEU o a ridurre la sua gravità. Tra queste misure vi è la precoce e generosa somministrazione di fluidi per contrastare la disidratazione e indurre una lieve espansione di volume. Inoltre, sebbene gli antibiotici siano tradizionalmente ritenuti controindicati nelle infezioni da STEC, recenti studi evidenziano che gli agenti che non inducono lisi batterica (ad es. azitromcina) potrebbero avere una valenza preventiva nei confronti dello sviluppo della SEU e terapeutica in chi l’ha sviluppata. Lo scopo del presente contributo è di condividere l’approccio clinico alla DEA e alle infezioni da STEC con un coinvolgimento di tutte le società scientifiche rilevanti per il contesto (AMCLI, SIGENP, SIMEUP, SIN, SIP, SIPPS, SITIP). L’obiettivo è quello di promuovere la diagnosi precoce dell’infezione da STEC attraverso lo screening di tutte le DEA con la biologia molecolare. Confidiamo che questo approccio possa aumentare la comprensione dei meccanismi di trasmissione dell’infezione da STEC riducendo, in ultimo, l’incidenza della SEU, la sua letalità e migliorandone l’outcome a breve e lungo termine.
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Bibliografia
1. Guarino A, Ashkenazi S, Gendrel D, Lo Vecchio A, Shamir R, Szajewska H; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Society for Pediatric Infectious Diseases. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases Evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014. J Pediatr Gastroenterol Nutr 2014;59(1):132-52. doi: 10.1097/MPG.0000000000000375.
2. Ardissino G, Vignati C, Masia C, et al.; ItalKid-HUS Network. Bloody Diarrhea and Shiga Toxin-Producing Escherichia coli Hemolytic Uremic Syndrome in Children: Data from the ItalKid-HUS Network. J Pediatr 2021; 237:34-40.e1. doi: 10.1016/j.jpeds.2021.06.048.
3. Terajima J, Izumiya H, Hara-Kudo Y, Ohnishi M. Shiga Toxin (Verotoxin)-producing Escherichia coli and Foodborne Disease: A Review. Food Saf (Tokyo) 2017;5(2):35-53. doi: 10.14252/foodsafetyfscj.2016029.
4. Ardissino G, Possenti I, Vignati C, et al. Is Shigatoxin 1 protective for the development of Shigatoxin 2-related hemolytic uremic syndrome in children? Data from the ItalKid-HUS Network. Pediatr Nephrol 2020;35(10): 1997-2001. doi: 10.1007/s00467-020-04697-y.
5. Ardissino G, Salardi S, Colombo E, et al. Epidemiology of haemolytic uremic syndrome in children. Data from the North Italian HUS network. Eur J Pediatr 2016;175(4):465-73. doi: 10.1007/s00431-015-2642-1.
6. Istituto Superiore di Sanità. Dati del Registro Italiano (www.epicentro.iss.it/).
7. Zoufaly A, Cramer JP, Vettorazzi E, et al. Risk factors for development of hemolytic uremic syndrome in a cohort of adult patients with STEC 0104:H4 infection. PLoS One 2013;8(3):e59209. doi: 10.1371/journal. pone.0059209.
8. Ko H, Maymani H, Rojas-Hernandez C. Hemolytic uremic syndrome associated with Escherichia coli O157:H7 infection in older adults: a case report and review of the literature. J Med Case Rep 2016;10:175. doi: 10.1186/s13256-016-0970-z.
9. Luini MV, Colombo R, Dodaro A, et al. Family Clusters of Shiga Toxin-producing Escherichia coli Infection: An Overlooked Source of Transmission. Data From the ItalKid-Hus Network. Pediatr Infect Dis J 2021;40(1):1-5. doi: 10.1097/INF.0000000000002877.
10. Snedeker KG, Shaw DJ, Locking ME, Prescott RJ. Primary and secondary cases in Escherichia coli O157 outbreaks: a statistical analysis. BMC Infect Dis 2009;9:144. doi: 10.1186/1471-2334-9-144.
11. Ria T, Mancuso MC, Daprai L, et al.; ItalKid-HUS Network. Vacation in Egypt associated with Shiga toxin-producing Escherichia coli infection in children and adolescents, northern Italy, 2023. Euro Surveill 2024;29(30):2400056. doi: 10.2807/1560-7917.ES.2024.29.30.2400056.
12. Joseph A, Cointe A, Mariani Kurkdjian P, Rafat C, Hertig A. Shiga Toxin-Associated Hemolytic Uremic Syndrome: A Narrative Review. Toxins (Basel) 2020;12(2):67. doi: 10.3390/toxins12020067.
13. Capone V, Mancuso MC, Tamburini G, Montini G, Ardissino G. Hemoglobinuria for the early identification of STEC-HUS in high-risk children: data from the ItalKid-HUS Network. Eur J Pediatr 2021;180(9):2791-5. doi: 10.1007/s00431-021-04016-z.
14. Grisaru S, Xie J, Samuel S, et al.; Alberta Provincial Pediatric Enteric Infection Team. Associations Between Hydration Status, Intravenous Fluid Administration, and Outcomes of Patients Infected With Shiga Toxin-Producing Escherichia coli: A Systematic Review and Meta-analysis. JAMA Pediatr 2017;171(1):68-76. doi: 10.1001/jamapediatrics.2016.2952.
15. Giordano P, Netti GS, Santangelo L, et al. A pediatric neurologic assessment score may drive the eculizumab-based treatment of Escherichia coli-related hemolytic uremic syndrome with neurological involvement. Pediatr Nephrol 2019;34(3):517-27. doi: 10.1007/s00467-018-4112-2.
16. Ardissino G, Tel F, Testa S, et al.; ItalKid-HUS Network. A simple prognostic index for Shigatoxin-related hemolytic uremic syndrome at onset: data from the ItalKid-HUS network. Eur J Pediatr 2018;177(11):1667-74. doi: 10.1007/s00431-018-3198-7.
17. Ardissino G, Tel F, Possenti I, et al. Early Volume Expansion and Outcomes of Hemolytic Uremic Syndrome. Pediatrics 2016;137(1). doi: 10.1542/peds.2015-2153.
18. Liu Y, Thaker H, Wang C, Xu Z, Dong M. Diagnosis and Treatment for Shiga Toxin-Producing Escherichia coli Associated Hemolytic Uremic Syndrome. Toxins (Basel) 2022;15(1):10. doi: 10.3390/toxins15010010.
19. Garnier A, Brochard K, Kwon T, et al. Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial. J Am Soc Nephrol 2023;34(9):1561-73. doi: 10.1681/ ASN.0000000000000182.
20. Freedman SB, Xie J, Neufeld MS, et al.; Alberta Provincial Pediatric Enteric Infection Team (APPETITE). Shiga Toxin-Producing Escherichia coli Infection, Antibiotics, and Risk of Developing Hemolytic Uremic Syndrome: A Meta-analysis. Clin Infect Dis 2016;62(10):1251-8. doi: 10.1093/cid/ciw099.
21. Tarr PI, Freedman SB. Why antibiotics should not be used to treat Shiga toxin-producing Escherichia coli infections. Curr Opin Gastroenterol 2022;38(1):30-8. doi: 10.1097/ MOG.0000000000000798.
22. Fukushima H, Hashizume T, Morita Y, et al. Clinical experiences in Sakai City Hospital during the massive outbreak of enterohemorrhagic Escherichia coli O157 infections in Sakai City, 1996. Pediatr Int 1999;41(2):213-7. doi: 10.1046/j.1442-200x.1999.4121041.x.
23. Myojin S, Pak K, Sako M, et al. Interventions for Shiga toxin-producing Escherichia coli gastroenteritis and risk of hemolytic uremic syndrome: A population-based matched case control study. PLoS One 2022;17(2): e0263349. doi: 10.1371/journal.pone.0263349.
24. Tajiri H, Nishi J, Ushijima K, et al. A role for fosfomycin treatment in children for prevention of haemolytic-uraemic syndrome accompanying Shiga toxin-producing Escherichia coli infection. Int J Antimicrob Agents 2015;46(5):586-9. doi: 10.1016/j.ijantimicag.2015.08.006.
25. Kimmitt PT, Harwood CR, Barer MR. Toxin gene expression by shiga toxin-producing Escherichia coli: the role of antibiotics and the bacterial SOS response. Emerg Infect Dis 2000;6(5):458-65. doi: 10.3201/ eid0605.000503.
26. Bielaszewska M, Idelevich EA, Zhang W, et al. Effects of antibiotics on Shiga toxin 2 production and bacteriophage induction by epidemic Escherichia coli O104:H4 strain. Antimicrob Agents Chemother 2012;56(6):3277-82. doi: 10.1128/AAC.06315-11.
27. Ohara T, Kojio S, Taneike I, et al. Effects of azithromycin on shiga toxin production by Escherichia coli and subsequent host inflammatory response. Antimicrob Agents Chemother 2002;46(11):3478-83. doi: 10.1128/ AAC.46.11.3478-3483.2002.
28. Berger M, Aijaz I, Berger P, Dobrindt U, Koudelka G. Transcriptional and Translational Inhibitors Block SOS Response and Shiga Toxin Expression in Enterohemorrhagic Escherichia coli. Sci Rep 2019;9(1):18777. doi: 10.1038/s41598-019-55332-2.
29. Ramstad SN, Taxt AM, Naseer U, Wasteson Y, Bjørnholt JV, Brandal LT. Effects of antimicrobials on Shiga toxin production in high-virulent Shiga toxin-producing Escherichia coli. Microb Pathog 2021;152:104636. doi: 10.1016/j.micpath.2020.104636.
30. Zhang Q, Donohue-Rolfe A, Krautz-Peterson G, Sevo M, Parry N, Abeijon C, Tzipori S. Gnotobiotic piglet infection model for evaluating the safe use of antibiotics against Escherichia coli O157:H7 infection. J Infect Dis 2009;199(4):486-93. doi: 10.1086/596509.
31. Agger M, Scheutz F, Villumsen S, Mølbak K, Petersen AM. Antibiotic treatment of verocytotoxin-producing Escherichia coli (VTEC) infection: a systematic review and a proposal. J Antimicrob Chemother 2015;70(9):2440-6. doi: 10.1093/jac/dkv162.
32. Sayk F, Hauswaldt S, Knobloch JK, Rupp J, Nitschke M. Do asymptomatic STEC-long-term carriers need to be isolated or decolonized? New evidence from a community case study and concepts in favor of an individualized strategy. Front Public Health 2024;12: 1364664. doi: 10.3389/fpubh.2024.1364664. 33. Nitschke M, Sayk F, Härtel C, et al. Association between azithromycin therapy and duration of bacterial shedding among patients with Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. JAMA 2012;307(10):1046-52. doi: 10.1001/jama.2012.264.
34. ArdissinoG, Dato L, MancusoMC, et al. Azithromycin for the Prevention of Hemolytic Uremic Syndrome in Shiga Toxin-Positive Diarrhea: A Proof of Concept. Journal of the American Society of Nephrology 2024; 35 (10S). doi: 10.1681/ASN.2024fmfgwrv7.
Corrispondenza: ardissino@centroseu.org