Immune Response to C.Difficile Infection

Study Overview
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Brief Summary
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The protocol aims to address the basic mechanisms of Clostridium difficile pathogenesis by identifying how a Th 17 response impacts severity of C. difficile infection and how Type II immunity protects the gut from Clostridium difficile toxin-induced damage. This could lead to new and effective approaches to the treatment or prevention of Clostridium difficile colitis that act downstream of fecal microbiota transplants (FMT) or next generation probiotics. Successful fecal microbial transplantation will restore protective immunity to recurrent C.difficile infection.

Detailed Description
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The study includes one cohort of hospitalized patients with acute CDI who may require diagnostic colonoscopy, a second cohort of outpatients with recurrent CDI scheduled for FMT and a third cohort of inpatients with past history of CDI without recurrence. Blood samples and discarded stool samples for research will be obtained from adult hospitalized patients. Biopsies and brushing samples for research will be obtained from patients requiring diagnostic colonoscopies for clinical care. Follow-up will include phone contact at 60-90 days to determine relapse or mortality in acute CDI patients. Blood and colonic biopsies and brushing samples will be obtained from patients undergoing FMT for recurrent CDI and again after 60 days from convalescent patients. Blood and biopsies taken for research purposes at each colonoscopy will be analyzed for: cytokines and chemokines, gene expression analysis, immunohistochemistry and high dimensional flow-cytometry.

Official Title
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Clostridioides Difficile and Immune Responses in Acute CDI and Fecal Microbiota Transplant

Conditions
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Clostridium Difficile

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Acute CDI cohort Acute CDI diagnosis including PCR positive fecal samples Optional diagnostic colonoscopy for clinical care FMT cohort At least one relapse or recurrence of C. difficile infection Eligible for fecal microbiota transplant (FMT) Past CDI cohort Past CDI diagnosis and current PCR negative fecal samples Optional diagnostic colonoscopy for clinical care Exclusion Criteria: Acute CDI cohort: Unwilling to have research biopsies and brushings at time of diagnostic colonoscopy; Unwilling to provide blood and stool samples (discarded stool from UVA lab) for research Unwilling to participate in follow-up phone call at 60-90 days Concurrent participation in another clinical trial. This exclusion does not apply to participation in IRB-HSR #200046 and non-interventional research studies. Concurrent participation in non-interventional research studies is allowed. Clinical contraindication to colonoscopy or conscious sedation Pregnancy Inability to give informed consent unless a legally authorized representative (LAR) is available Incarceration HIV infection FMT cohort: Unwilling to have research biopsies and brushings and stool samples at time of colonoscopy with FMT for clinical care and research sigmoidoscopy at Day 60 Unwilling to provide blood samples for research Concurrent participation in another clinical trial This exclusion does not apply to participation in non-interventional research studies. Concurrent participation in non-interventional research studies is allowed. Clinical contraindication to sigmoidoscopy or conscious sedation Pregnancy Inability to give informed consent Incarceration HIV infection Neutropenia (<1000 PMNs/µl blood) Past CDI Control cohort: Unwilling to have research biopsies and brushings at time of diagnostic colonoscopy; Unwilling to provide blood and stool samples (discarded stool from UVA lab) for research Concurrent participation in another clinical trial. This exclusion does not apply to participation in IRB-HSR #200046 and non-interventional research studies. Concurrent participation in non-interventional research studies is allowed. Clinical contraindication to colonoscopy or conscious sedation Pregnancy Inability to give informed consent unless a legally authorized representative (LAR) is available Incarceration HIV infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Acute CDI cohort<br>Hospitalized patients diagnosed with Acute CDI | |
| FMT cohort<br>Patients undergoing FMT for recurrent CDI | |
| Past CDI Control Cohort<br>Hospitalized patients with past CDI diagnosis without recurrence | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adaptive immune response | Assessment of adaptive immunity including Th1, Th2 and TH17 immune response | 0-60 days post enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in gut health | Association of biomarkers in stool and biopsy specimens with CDI outcome | 0-60 days post enrollment | 
| Gene expression of immune cells in colon | Profiling colonic gene expression and mucosal immune pathways in CDI | 0-60 days post enrollment | 
| Microbiome | Tissue 16s rDNA | 0-60 days post enrollment | 
| Immunohistochemistry | Changes in mucosal immunity following FMT | 0-60 days post enrollment | 
| Antibody response to C. difficile infection | IgG and IgA to C. difficile antigens in plasma and stool | 0-60 days post enrollment | 
| High dimensional flow-cytometry | Profiling of immune cells in blood and biopsy | 0-60 days post enrollment |