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Aspetti eziopatogenetici e clinici delle infezioni intestinali
Sarmati L
Università Tor Vergata, Roma
Circolazione ed impatto dei patogeni enterici in Italia - 18 ottobre 2018
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My disclosures
I received travel grants from Gilead, Merck, Gilead, Bristol, Pfizer payment for lectures from Merck, Gilead, Bristol, Pfizer Abbvie research funding from Gilead
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Gastroenteritis is inflammation of the stomach, small intestine, or large intestine, leading to a combination of abdominal pain, cramping, nausea, vomiting, and diarrhea. Acute gastroenteritis usually lasts fewer than 14 days. This is in contrast to persistent gastroenteritis, which lasts between 14 and 30 days, and chronic gastroenteritis, which lasts more than 30 days
Nancy S. Graves , Prim Care Clin Office Pract 2013
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WHO data on safe food 2015
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MMWR / March 23, 2018
In 2017, FoodNet reported 24,484 infections, 5,677 hospitalizations, and 122 deaths. Compared with 2014–2016, the 2017 incidence of infections with Campylobacter, Listeria, non-O157 Shiga toxin–producing Escherichia coli (STEC), Yersinia, Vibrio, and Cyclospora increased.
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Climatic factors influence the growth and survival of pathogens, as well as transmission pathways. Higher ambient temperatures increase replication cycles of food-borne pathogens, and prolonged seasons may augment the opportunity for food handling mistakes - in 32% of investigated food-borne outbreaks in Europe “temperature misuse” is considered a contributing factor
Confalonieri UE, Menezes JA, Margonari de Souza C. Climate change and adaptation of the health sector: The case of infectious diseases. Virulence. 2015
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VIRAL: 50-70% BACTERIAL: 15-20% PARASITIC: 10-15%
Norovirus Shigella Giardia
Rotavirus Salmonella Amebiasis
Enteric Adenovirus type 40, 41
Campylobacter Cryptosporidium
Astrovirus E.coli Isospora
Coronavirus Vibrio Cyclospora
Some picornavirus Yersina Microsporidium
C. difficile
Infectious causes of gastroenteritis
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Gastroenterite (Diarrea) infettiva
La diarrea infettive da un punto di vista patogenetico/clinico viene suddiviso in 2 gruppi
1. diarrea non infiammatoria
2. diarrea infiammatoria
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Diarrea non infiammatoria Diarrea Infiammatoria
Generalmente meno grave Generalmente più grave
Diarrea senza sangue , spesso acquosa, senza febbre e senza evidenti dolori addominali
Spesso diarrea con sangue evidente, forti dolori addominali e febbre
Assenza di leucociti e sangue occulto all’esame microscopico delle feci
Presenza di un rilevante numero di leucociti nelle feci
Generalmente causate da: Rotavirus, Norovirus, S. aureus, Bacillus cereus, Clostridium perfrigens, cryptosporidium parvum e Giarda lamblia
Causata tipicamente da patogeni invasivi quali: Campylobacter Jeiuni, Shigella species, Salmonella species, Clostridium difficile, Shiga toxin-producing E. coli (STEC) e Entamoeba histolytica
La maggioranza dei casi richiede esclusivamente terapia reidratante
Spesso necessario trattamento antibiotico specifico
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An overview of general mechanisms causing diarrhea
Cistic fibrosis transmembrane conductance regulator (CFTR) and calcium activated chloride channel(CLCA) are chloride channels. Na+/H+ exchange isoform, NHE3, is involved in Na+ absorption. Exchander down regulated in adenoma (DRA) is responsible for chloride absorption. Aquaporins seem to contribute to diarrhea when absorption is reduced. SGLT-1 transports sodium and glucose
Hodges 2010
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Diarrea non infiammatoria : vibrione del colera
Subunits A and B
Le subunità B permettono l’entrata delle subunità A GTPase AMPc CFTR rilascio di CL l’inibizione di NHE 2-3 di Na con conseguente liberazione di NaCl nel lume e aumento della secrezione e riduzione dell’assorbimento. Le altre tossine VCC (citolisina) facilita l’uscita di cloro aumentando la permeabilità e ACE (accessory colera toxin)che determina la secrezione ci Cl calcio mediata. Zot e RTX alterano le giunzioni cellulari
Hodges 2010
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Antibiotic-induced alterations in gut microbial metabolism decrease colonization resistance against C. difficile
(a) Primary bile acids (e.g., conjugated, TCA, and unconjugated, CA) were absorbed in the terminal ileum (95%). The small amount of TCA e CA reaches the large intestine where is biotransformed by gut microbiota in secondary bile acids, DCA, LCA, and UDCA. C. difficile spores can use primary bile acids TCA and CA in the ileum for germination . The presence of secondary bile acids and competition from other members of the indigenous gut microbiota are able to inhibit C. difficile outgrowth and colonization. (b) Antibiotic treatment specifically decreasie bacteria that are able to deconjugate and dehydroxylate primary bile acids into secondary bile acids, as shown in the striped red box
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Diarrea non infiammatoria : Clostridium difficile
C. difficile produces toxin A and toxin B (TcdA and TcdB). TcdA causes cytoskeletal modification and disruption of tight junctions. The resulting loss of epithelial barrier function facilitates TcdA and TcdB to cross the. Both toxins are cytotoxic and lead to production of proinflammatory cytokines, increase in vascular permeability, recruitment of neutrophils and monocytes, epithelial cell apoptosis and connective tissue degradation, resulting in pseudomembrane formation and diarrhea.
Hodges 2010
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Diarrea infiammatoria : Shigella spp
La shigella deve la sua citossicità all’azione di plasmidi inoltre le actin tails facilitano la sua penetrazione . LPS attiva la risposta infiammatoria attivando TLR4 e poi IL6 e IL8. IL8 è un forte attivatore dei leucociti
Hodges 2010
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Aspetti clinici delle gastroenteriti infettive
Sintomi
• diarrhea.
• nausea and vomiting.
• headache, muscle aches, or joint aches.
• fever or chills.
• sweating or clammy skin.
• abdominal cramps and pain.
• loss of appetite.
Complicanze possibili
• Dehydration
• Malabsorption
• Transient lactose intolerance
• Systemic infection: sepsis, arthritis, pneumonia, etc. (Salmonella, Yersinia, Campylobacter organisms)
• Hemolytic-uremic syndrome (in children with E coli O157:H7)
• Toxic megacolon
• Persistent diarrhea
• Thrombotic thrombocytopenic purpura TTP (E coli O157:H7)
• Guillain-Barré syndrome (Campylobacter organisms)
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Organism Incubation Duration Vomiting Fever Abdominal
Pain
Aeromonas species None 0-2 weeks +/- +/- No
Bacillus species 1-16 hours 1-2 days Yes No Yes
Campylobacter species 2-4 days 5-7 days No Yes Yes
C difficile Variable Variable No Few Few
C. perfringens 0-1 1 day Mild No Yes
Enterohemorrhagic E coli
1-8 days 3-6 days No +/- Yes
Enterotoxigenic E coli 1-3 days 3-5 days Yes Low Yes
Listeria species 20 hours 2 days Few Yes +/-
Plesiomonas species None 0-2 weeks +/- +/- +/-
Salmonella species 0-3 days 2-7 days Yes Yes Yes
Shigella species 0-2 days 2-7 days No High Yes
S aureus 2-6 hours 1 day Yes No Yes
Vibrio species 0-1 days 5-7 days Yes No Yes
Y. enterocolitica 0-6 1-46 days Yes Yes Yes
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Diagnosi delle infezioni intestinali
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Stool characteristics
Small Bowel Large Bowel
Appearance Watery Mucus and/or blood
Volume Large Small
Frequency Increased Increased
Blood Heme-positive but not gross blood Possibly grossly bloody
pH Possibly < 5.5 >5.5
Reducing substances Possibly positive Negative
WB cells count < 5/high-power field (HPF) Possibly >10/HPF
Serum WBC count Normal Possible leukocytosis,
Organisms
Preformed toxins: Bacillus species, Staphylococcus aureus
Invasive bacteria: E coli, Shigella,Salmonella,Campylobacter,Yersinia, Aeromonas, Plesiomonas
Toxic bacteria: E coli, cholera, C. perfringens, Vibrio species, Listeria
Toxic bacteria: C difficile
Other causes: rotavirus, adenovirus, calicivirus, astrovirus, Norwalk virus, Giardia and Cryptosporidium species
Other causes: Entamoeba species
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Organism Detection Method Microbiologic Characteristics
Aeromonas species Blood agar Oxidase-positive, flagellated GNB
Bacillus species Blood agar Spore-forming GPR; beta hemolytic; reduces nitrates;
Campylobacter spp Skirrow agar Rapidly motile, curved GNR; Campylobacter jejuni 90% of infections,
C difficile CCFE agar, EIA for toxin, LA for protein
Anaerobic, spore-forming GPR; toxin-mediated diarrhea
C perfringens None available Anaerobic, spore-forming GPR; toxin-mediated diarrhea
E coli MacConkey, EMB, or SM agar Lactose-producing GNR
Listeria species Blood agar Flagellated GPB
Plesiomonas spp Blood agar Oxidase-positive GNR
Salmonella spp Blood, MacConkey, EMB, XLD, or HE agar
Nonlactose, non–H2S-producing GNR
Shigella spp Blood, MacConkey, EMB, XLD, or HE agar
Nonlactose and H2S-producing GNR; verotoxin (neurotoxin)
Staphylococcus spp Blood agar Heat-stable, preformed toxin
Vibrio species Blood or TCBS agar Oxidase-positive, motile, curved GNB
Y enterocolitica CIN agar Nonlactose-producing, oval GNR
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Breese JS et al JID 2012
A prospective, multicenter emergency department–based study of adults with AGE. Subjects were interviewed on presentation and 3–4 weeks later. Serum samples, rectal swab specimens were collected at presentation and (serum)3–4 weeks later. Fecal specimens were tested for a panel of
viral, bacterial, and parasitic pathogens.
Pathogens were detected in
25% of 364 subjects
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A variety of commercially available nucleic acid amplification platforms are capable of targeting multiple microorganisms in a single test reaction so identify the most frequent causes of infectious diseases directly from clinical specimens. Available evidence suggests that the analytical performance of current GI panels is essentially equivalent. Analytical specificity has exceeded 98% for all targets with rare exceptions. Sensitivity characteristics have been more variable, however, with values ranging from 90% to 100%. The rapidity of multiplex tests compared to that of conventional methods is one of the major advantages of molecular testing
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Clinical Infectious Diseases® 2016
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Clinical Infectious Diseases® 2016
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MMWR / March 23, 2018
CIDT = culture-independent diagnostic test;
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Goldenberg J Infection 2015
the Luminex xTAG Gastrointestinal Pathogen Panel (GPP)
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Grazie