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Martinato, Matteo (2013) Uno studio prospettico sull'infezione da Clostridium difficile nelle malattie infiammatorie croniche intestinali: fattori di rischio, tossino-tipi, sensibilitĂ  agli antibiotici, capacitĂ  di adesione e impatto sul successivo decorso della malattia. [Tesi di dottorato]

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Abstract (inglese)

Clostridium difficile is a Gram positive bacterium rarely present in normal human gut flora that under certain conditions of intestinal dysbiosis, in patients treated with broad-spectrum antibiotics, in hospitalized patients, in immunocompromised subjects and elderly, can cause disease of variable severity referred to as Clostridium Difficile Associated Diarrohea (CDAD). Although in the past Clostridium difficile has been indicated as a possible causal factor in the development of inflammatory bowel disease (also known as IBD), nowadays it is more likely to believe that the IBD may be a risk factor for Clostridium difficile infection (CDI).
CDI in patients with IBD is of increasing importance because the frequency with which it occurs is growing over time, but also because it seems to have a negative impact on health outcomes and because the symptoms induced CDI are indistinguishable from that of an exacerbation of IBD: it is therefore essential to establish an early diagnosis in order to start the most suitable treatment of the case.
The aim of this study was to describe the frequency of the CDI in healthy subjects, subjects not affected by IBD hospitalized with suspected CDAD and patients with IBD, characterize strains of Clostridium difficile isolated from IBD patients (sensitivity to antibiotics, types of toxins, adhesion to the intestinal epithelium), to identify risk factors for CDI in IBD patients (characteristics of the subject, illness, concomitant therapy) and to assess the impact of CDI on the course of IBD, both in symptomatic and asymptomatic carriers.
From January 2010, stool samples from IBD outpatients and inpatients were collected and analyzed at the Gastroenterology unit of the University Hospital of Padua (both in the acute phase of disease and in remission), from patients admitted to the same unit without IBD but with symptoms and medical treatment suggestive of CDAD and from a control group of healthy subjects matched for age and sex.
From the first evaluation (and the collection of the first stool sample), patients with IBD were evaluated at least every six months or in case of relapse or hospitalization for two years. On each sample an anaerobic culture was performed, followed by specific PCR to identify any colonies of Clostridium difficile. Each strain was then characterized by:
- Toxins production
- Antibiotics sensitivity
- Adhesion to Caco-2 cells
- Presence or absence of the tcdC gene in bacterial DNA
Clinical data were collected from patients with IBD to identify any risk factors for CDI.
Patients with IBD have a higher frequency of colonization by Clostridium difficile than the control group: in healthy subjects CDI was detected in 0/55 subjects, in hospitalized IBD patients was found in 5/55 patients (9%) and in IBD outpatients was detected in 9/195 subjects (4.6%).
The production profile of the toxins appears to be different in IBD and non-IBD patients with antibiotic-associated diarrhea, confirming the hypothesis of community-acquired strains rather than hospital-acquired.
Antibiotics sensitivity tests performed on strains isolated from patients with CDAD and patients with IBD showed that all strains are sensitive to metronidazole and vancomycin and markedly resistant to ciprofloxacin.
Strains of Clostridium difficile isolated from patients with active IBD, in remission and from patients with CDAD have shown a different, albeit small, ability to adhere to monolayers of human intestinal epithelial cells (Caco-2), suggesting that strains from active IBD patients have a greater ability to colonize than those from patients in remission.
The tcdC gene was identified in 8% of toxigenic strains isolated from IBD patients (active and in remission) and in 25% of those isolated from patients with CDAD, but the genome had deletions of varying extent, indicating a potential increased virulence of identified strains.
The statistical analysis did not identify any risk factor associated with CDI in IBD.
In the prospective study, CDI has not been identified as a risk factor for clinical or endoscopic relapse or for the need for surgical treatment, demonstrating instead, unexpectedly, to have a protective role against disease flare.

Abstract (italiano)

Il Clostridium difficile è un batterio Gram positivo raramente presente nella normale flora intestinale umana che in particolari condizioni di disbiosi intestinale, in pazienti trattati con antibiotici ad ampio spettro, in pazienti ospedalizzati, in soggetti immunocompromessi e in persone anziane, può causare patologie di variabile gravità indicate complessivamente come Clostridium difficile Associated Diarrohea (CDAD). Sebbene in passato il Clostridium difficile sia stato indicato come possibile concausa dello sviluppo delle malattie infiammatorie croniche intestinali (note anche come inflammatory bowel disease, IBD), oggi si è più propensi a ritenere che le IBD possano
essere un fattore di rischio per l’infezione da Clostridium difficile (CDI). La CDI nei pazienti affetti da IBD riveste una sempre maggiore importanza, sia perché la
frequenza con cui si presenta stà crescendo nel tempo, sià perché sembra determinare un impatto negativo sugli outcome di salute, ma anche perché la sintomatologia indotta dalla CDI è indistinguibile da quella di una riacutizzazione della IBD: è quindi fondamentale una diagnosi tempestiva per instaurare le terapie più idonee al trattamento del caso.
Lo scopo dello studio è descrivere la frequenza della CDI in soggetti sani, soggetti non affetti da IBD ospedalizzati con sospetto di CDAD e soggetti affetti da IBD, caratterizzare i ceppi di Clostridium difficile isolati da pazienti IBD (sensibilità agli antibiotici, tipologie di tossine prodotte, capacità di adesione all’epitelio intestinale), identificare i fattori di rischio per la CDI nei pazienti IBD (caratteristiche del soggetto, della malattia, della terapia concomitante) e valutare l'impatto della CDI sul decorso della IBD, sia nei portatori sintomatici che in quelli asintomatici.
Da gennaio 2010 sono stati raccolti ed analizzati campioni da pazienti IBD ambulatoriali o degenti presso l’unità operativa complessa di gastroenterologia dell’Azienda Ospedaliera di Padova (sia in fase acuta di malattia che in remissione), da pazienti ricoverati presso la medesima unità operativa non affetti da IBD con sintomi e terapia medica suggestivi di CDAD e da un gruppo di controllo di soggetti sani appaiati per età e sesso.
Dalla prima valutazione (e della raccolta del primo campione) i pazienti con IBD sono stati valutati almeno ogni sei mesi o in caso di recidiva o di ricovero ospedaliero per due anni. Su ogni campione è stata eseguita una coltura anaerobica seguita da PCR specifica per identificare eventuali colonie di C. difficile. Ogni ceppo è stato poi caratterizzato in base a:
- tossine prodotte
- sensibilitĂ  agli antibiotici
- adesione alle cellule Caco-2
- presenza o assenza del gene tcdC nel DNA batterico
Dati clinici sono stati raccolti dai pazienti con IBD per identificare eventuali fattori di rischio per la CDI.
I pazienti con IBD sembrano presentare una maggiore frequenza di colonizzazione da parte del Clostridium difficile rispetto al gruppo di controllo dei soggetti sani: nei controlli la CDI è stata rilevata in 0/55 soggetti. Nei pazienti ricoverati con IBD è stata trovata in 5/55 soggetti (9%). Nei pazienti ambulatoriali è stata rilevata in 9/195 soggetti (4,6%).
Il profilo di produzione delle tossine sembra essere differente nei pazienti IBD e nei pazienti non-IBD con diarrea da antibiotici, confermando l'ipotesi di ceppi acquisiti in comunitĂ  e non in ambiente ospedaliero.
L’antibiogramma eseguito su ceppi isolati da pazienti con CDAD e pazienti con IBD attive o in remissione ha mostrato che tutti i ceppi sono sensibili a metronidazolo e vancomicina e marcatamente resistenti alla ciprofloxacina.
Ceppi di Clostridium difficile isolati da pazienti con IBD attive, in fase di remissione e da pazienti con CDAD hanno dimostrato una diversa, seppur piccola, capacitĂ  di aderire a monostrati di cellule epiteliali intestinali umane (CACO-2), indicando che i ceppi associati ai pazienti con IBD attive hanno maggiore abilitĂ  a colonizzare di quelli in remissione.
Il gene tcdC è stato identificato nell’8% dei ceppi tossigenici isolati da pazienti IBD (attivi ed in remissione) e nel 25% di quelli isolati da pazienti con CDAD, ma il genoma presentava delezioni di varia entità, indicando una potenziale aumentata virulenza dei ceppi identificati.
L'analisi statistica non ha individuato fattori di rischio associati con la CDI.
Nella parte prospettica dello studio la CDI non è stata identificata come fattore di rischio per la recidiva clinica o endoscopica o per la necessità di trattamento chirurgico, dimostrando invece, inaspettatamente, di avere un ruolo protettivo nei confronti della riacutizzazione della malattia.

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Tipo di EPrint:Tesi di dottorato
Relatore:Sturniolo, Giacomo Carlo
Dottorato (corsi e scuole):Ciclo 25 > Scuole 25 > BIOLOGIA E MEDICINA DELLA RIGENERAZIONE > SCIENZE EPATOLOGICHE E GASTROENTEROLOGICHE
Data di deposito della tesi:30 Gennaio 2013
Anno di Pubblicazione:31 Gennaio 2013
Parole chiave (italiano / inglese):Clostridium difficile inflammatory bowel disease
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/07 Microbiologia e microbiologia clinica
Area 06 - Scienze mediche > MED/12 Gastroenterologia
Area 06 - Scienze mediche > MED/45 Scienze infermieristiche generali, cliniche e pediatriche
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Chirurgiche Oncologiche e Gastroenterologiche
Codice ID:5821
Depositato il:15 Ott 2013 14:04
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