Aspetti eziopatogenetici e clinici delle infezioni intestinali

Sarmati L

Università Tor Vergata, Roma

Circolazione ed impatto dei patogeni enterici in Italia - 18 ottobre 2018

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

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

WHO data on safe food 2015

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.

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

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

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

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

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

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

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

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

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

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)

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

Diagnosi delle infezioni intestinali

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

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

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

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

Clinical Infectious Diseases® 2016

Clinical Infectious Diseases® 2016

MMWR / March 23, 2018

CIDT = culture-independent diagnostic test;

Goldenberg J Infection 2015

the Luminex xTAG Gastrointestinal Pathogen Panel (GPP)

Grazie