Publications by authors named "Darrell S Pardi"

183 Publications

Development of Gastroenterology and Transplant Hepatology Milestones 2.0: A Guide for Programs, Faculty, and Fellows.

Gastroenterology 2021 Oct 7;161(4):1318-1324. Epub 2021 Sep 7.

Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina.

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http://dx.doi.org/10.1053/j.gastro.2021.07.040DOI Listing
October 2021

Development of gastroenterology and transplant hepatology milestones 2.0: a guide for programs, faculty, and fellows.

Gastrointest Endosc 2021 Oct 7;94(4):665-670. Epub 2021 Sep 7.

Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.

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http://dx.doi.org/10.1016/j.gie.2021.04.019DOI Listing
October 2021

Development of Gastroenterology and Transplant Hepatology Milestones 2.0: A Guide For Programs, Faculty, and Fellows.

Hepatology 2021 Oct 7;74(4):2226-2232. Epub 2021 Sep 7.

Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC.

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http://dx.doi.org/10.1002/hep.32097DOI Listing
October 2021

Development of gastroenterology and transplant hepatology milestones 2.0: a guide for programs, faculty, and fellows.

Am J Gastroenterol 2021 Sep 7. Epub 2021 Sep 7.

Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.

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http://dx.doi.org/10.14309/ajg.0000000000001490DOI Listing
September 2021

Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium.

Lancet Gastroenterol Hepatol 2021 10 18;6(10):826-849. Epub 2021 Aug 18.

Division of Gastroenterology, Hepatology, and Nutrition, Allegheny Health Network, Pittsburgh, PA, USA.

Restorative proctocolectomy with ileal pouch-anal anastomosis is an option for most patients with ulcerative colitis or familial adenomatous polyposis who require colectomy. Although the construction of an ileal pouch substantially improves patients' health-related quality of life, the surgery is, directly or indirectly, associated with various structural, inflammatory, and functional adverse sequelae. Furthermore, the surgical procedure does not completely abolish the risk for neoplasia. Patients with ileal pouches often present with extraintestinal, systemic inflammatory conditions. The International Ileal Pouch Consortium was established to create this consensus document on the diagnosis and classification of ileal pouch disorders using available evidence and the panellists' expertise. In a given individual, the condition of the pouch can change over time. Therefore, close monitoring of the activity and progression of the disease is essential to make accurate modifications in the diagnosis and classification in a timely manner.
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http://dx.doi.org/10.1016/S2468-1253(21)00101-1DOI Listing
October 2021

Clinical Characteristics and Treatment Response in Microscopic Colitis Based on Age at Diagnosis: A Multicenter Retrospective Study.

Dig Dis Sci 2021 Jul 20. Epub 2021 Jul 20.

Division of Gastroenterology and Hepatology, Massachusetts General Hospital, Boston, MA, USA.

Background: Microscopic colitis (MC) primarily affects older adults; thus, data in younger patients are scarce.

Aims: To compare clinical characteristics and treatment response by age at diagnosis.

Methods: This retrospective cohort study was performed at Mayo Clinic and Massachusetts General Hospital. Patients were chosen consecutively using established databases. Patients were 'younger' if age at diagnosis was ≤ 50 years and 'older' if age > 50 years. Treatment outcomes were captured for induction (12 ± 4 weeks), based on the total number of daily stools, and defined as remission (complete resolution), response (≥ 50% improvement), non-response (< 50% improvement), and intolerance. Patients were considered 'responders' if they had remission or response and 'non-responders' if they had non-response or intolerance.

Results: We included 295 patients (52 younger, 243 older). There were no differences in sex, race, MC subtype, and diarrhea severity between groups (all P > 0.05). Younger patients were more likely to have celiac disease (17.3% vs. 5.8%, P = 0.01), while older patients had higher BMI (mean 25.0 vs. 23.8 kg/m, P = 0.04) were more likely smokers (53.9% vs. 34.6%, P = 0.01) and use NSAIDs (48.6% vs. 15.4%, P < 0.01) and statins (22.6% vs. 3.8%, P < 0.01). Overall treatment response was highest for budesonide (88.3%) and did not differ when comparing older to younger patients (90.6% vs. 77.8%, P = 0.12) or by MC subtype (LC, 81.5% vs. CC, 92.9%, P = 0.07).

Conclusions: There are no significant differences in MC treatment response based on age or disease subtype. These findings support treating patients with MC based on symptom severity rather than age.
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http://dx.doi.org/10.1007/s10620-021-07162-4DOI Listing
July 2021

The Epidemiology of Microscopic Colitis in Olmsted County, Minnesota: Population-Based Study From 2011 to 2019.

Clin Gastroenterol Hepatol 2021 Jun 30. Epub 2021 Jun 30.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background & Aims: Epidemiologic studies from Europe and North America have reported an increasing incidence of microscopic colitis (MC) in the late 20th century, followed by a plateau. This population-based study assessed recent incidence trends and the overall prevalence of MC over the past decade.

Methods: Residents of Olmsted County, MN, diagnosed with collagenous colitis (CC) or lymphocytic colitis (LC) between January 1, 2011, and December 31, 2019 were identified using the Rochester Epidemiology Project. Clinical variables were abstracted by chart review. Incidence rates were age- and sex-adjusted to the 2010 US population. Associations between incidence and age, sex, and calendar periods were evaluated using Poisson regression analyses.

Results: A total of 268 incident cases of MC were identified with a median age at diagnosis of 64 years (range, 19-90 y); 207 (77%) were women. The age- and sex-adjusted incidence of MC was 25.8 (95% CI, 22.7-28.9) cases per 100,000 person-years. The incidence of LC was 15.8 (95% CI, 13.4-18.2) and CC was 9.9 (95% CI, 8.1-11.9) per 100,000 person-years. A higher MC incidence was associated with increasing age and female sex (P < .01). There was no significant trend in age- and sex-adjusted incidence rate over the study period (P = .92). On December 31, 2019, the prevalence of MC, LC, and CC (including cases diagnosed before 2011) was 246.2, 146.1, and 100.1 per 100,000 persons, respectively.

Conclusions: The incidence of MC and its subtypes was stable between 2011 and 2019, but its prevalence was higher than in previous periods. The incidence of MC continues to be associated with increasing age and female sex.
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http://dx.doi.org/10.1016/j.cgh.2021.06.027DOI Listing
June 2021

Reply.

Gastroenterology 2021 Oct 24;161(4):1345. Epub 2021 Jun 24.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1053/j.gastro.2021.06.048DOI Listing
October 2021

Microscopic colitis.

Nat Rev Dis Primers 2021 06 10;7(1):39. Epub 2021 Jun 10.

Gastroenterology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Microscopic colitis (MC) is an inflammatory disease of the large intestine associated with urgent watery diarrhoea. MC may occur in people of all ages, although the disease primarily affects older women. Once believed to be rare, MC is now known to be a common cause of chronic watery diarrhoea in high-income countries, affecting 1 in 115 women and 1 in 286 men during their lifetime in Swedish population-based estimates. An inappropriate immune response to disturbances in the gut microenvironment is implicated in the pathogenesis of MC. Evidence also supports an underlying genetic basis for disease. The diagnosis of MC relies on clinical symptoms and microscopic assessment of colonic biopsy samples. MC is categorized histologically into collagenous colitis, lymphocytic colitis and their incomplete forms. The mainstay of treatment includes the use of budesonide, with or without adjunctive therapies, and withdrawal of offending drugs. Emerging studies suggest a role for biologicals and immunosuppressive therapies for the management of budesonide-refractory or budesonide-dependent disease. MC can have a substantial negative effect on patient quality of life. The outlook for MC includes a better understanding of the immune response, genetics and the microbiome in disease pathogenesis along with progress in disease management through robust clinical trials.
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http://dx.doi.org/10.1038/s41572-021-00273-2DOI Listing
June 2021

Fecal Microbiota Transplantation for Recurrent C difficile Infection During the COVID-19 Pandemic: Experience and Recommendations.

Mayo Clin Proc 2021 06;96(6):1418-1425

Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

Objective: To report experience with fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (rCDI) and provide recommendations for management of rCDI and donor testing during the COVID-19 pandemic.

Methods: A retrospective study of patients with rCDI who underwent FMT from May 26, 2020, to September 30, 2020, with stool from well-screened donors with health and infectious screening and a newly implemented strategy for COVID-19 screening with every 2-week bookend testing with stool quarantine. Patients were followed up for development of rCDI and COVID-19.

Results: Of the 57 patients who underwent FMT for rCDI, 29 were tested for COVID-19 via nasopharyngeal polymerase chain reaction (PCR) and 22 via serology. All results were negative, except for 1 positive serology. Donor testing every 2 weeks for COVID-19 via serology and nasopharyngeal swab PCR was negative, except for 2 donors at 1 center who were excluded. Three patients had rCDI after FMT, and 1 underwent repeat FMT. One patient developed respiratory symptoms suggestive of COVID-19 and tested negative via nasopharyngeal PCR. Eleven patients who underwent COVID-19 testing for elective procedures or hospitalizations tested negative. No SARS-CoV-2 transmission was noted.

Conclusions: With appropriate donor screening, FMT can be performed safely for rCDI during the COVID-19 pandemic. Development of a validated stool assay for SARS-CoV-2 will simplify this process further.
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http://dx.doi.org/10.1016/j.mayocp.2021.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169126PMC
June 2021

Microscopic Colitis and Risk of Colon Adenomas: A Multicenter Retrospective Cohort Study.

Clin Gastroenterol Hepatol 2021 May 29. Epub 2021 May 29.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Microscopic colitis (MC) is a common cause of chronic watery diarrhea, with the highest incidence in women over age 50. Cross-sectional studies have suggested that patients with MC have a lower incidence of adenomatous colon polyps compared with those without MC. The existing literature is limited by cross-sectional design, small sample sizes, lack of longitudinal follow-up, and the use of average-risk patients, rather than those with chronic diarrhea, as controls. We aimed to explore the association between MC and colon adenomas.
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http://dx.doi.org/10.1016/j.cgh.2021.05.050DOI Listing
May 2021

Microscopic Colitis: A Concise Review for Clinicians.

Mayo Clin Proc 2021 05;96(5):1302-1308

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. Electronic address:

Microscopic colitis (MC) is an inflammatory disease of the colon and a common cause of chronic watery diarrhea, predominantly in older patients. Microscopic colitis encompasses 2 different subtypes, lymphocytic colitis and collagenous colitis. The colon typically appears normal endoscopically in MC, and the diagnosis requires histologic evaluation. Whereas recent studies suggest that the incidence of MC has plateaued, given the aging of the population, the prevalence of MC will likely increase. Risk factors for MC include increasing age; female sex; presence of other autoimmune diseases; and possibly use of certain medications, including proton pump inhibitors, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, and statins. The clinical presentation of MC is nonspecific and includes watery nonbloody diarrhea, nocturnal stools, fecal urgency, abdominal pain, arthralgias, and weight loss. The disease course of MC is variable; some patients experience occasional, intermittent symptoms, and others demonstrate more chronic and even progressive symptoms. The approach to treatment is similar for both lymphocytic colitis and collagenous colitis and should be guided by the severity of the patient's symptoms. Offending medications highly associated with MC should be eliminated as clinically possible. In patients with mild symptoms, antidiarrheals such as loperamide are the initial choice; for moderate-severe disease, budesonide is recommended for induction of clinical remission. In those with recurrent symptoms, low-dose budesonide may be required for maintenance therapy with close monitoring for potential adverse effects. In rare cases, immunomodulators may be required.
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http://dx.doi.org/10.1016/j.mayocp.2021.03.022DOI Listing
May 2021

Outcomes in Patients with SARS-CoV-2 and Coinfection.

Infect Drug Resist 2021 28;14:1645-1648. Epub 2021 Apr 28.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Background: Coronavirus infectious disease 2019 (COVID-19) is primarily a respiratory disease. However, it may manifest with gastrointestinal symptoms that may overlap with infection (CDI). COVID-19 appears to have higher mortality in those with comorbidities. We aimed to assess the outcomes of coinfection in these patients.

Methods: A retrospective chart review was conducted to identify patients with CDI and COVID-19 from January 1st, 2020 to November 17th, 2020. Both infections were diagnosed via PCR. Clinical features, treatment for COVID-19 and CDI and outcomes including intensive care unit admission, colectomy, 30 day-mortality and long-term complications were analyzed.

Results: Overall, 21 patients (20 hospitalized) with median age 70.9 years (range 51.8-90.7 years) had CDI and COVID-19 within 4 weeks of each other. Of these, 4 patients (19%) with CDI were diagnosed with COVID-19 at the time of admission, 12 (57%) had CDI diagnosed after COVID-19, and 5 (23.9%) developed COVID-19 within 4 weeks after CDI. Fourteen patients (66.7%) were treated with medications directed against COVID-19 including remdesivir and dexamethasone (n=7), remdesivir with convalescent plasma (n= 1), remdesivir (n= 5) and dexamethasone (n=1). The most common treatment for CDI was oral vancomycin in 20 patients (95.2%), and 1 patient received intravenous metronidazole. No patient required colectomy for CDI but 2 (9.5%) required ICU admission. Four patients (19%) died likely due to COVID-19 with median age 80 years (range 61-90 years).

Conclusion: The relationship between COVID-19 and CDI is poorly understood, and studies are required to further investigate this association. Whether coinfection results in a worsening of outcomes, including mortality and clinical course, are questions that should be answered in future research studies. Diagnosing both infections for appropriate management is vital in light of overlapping symptoms.
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http://dx.doi.org/10.2147/IDR.S305349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089469PMC
April 2021

Medication use and microscopic colitis: a multicentre retrospective cohort study.

Aliment Pharmacol Ther 2021 06 14;53(11):1209-1215. Epub 2021 Apr 14.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York City, NY, USA.

Background: Medication use has been implicated in the development of microscopic colitis (MC). However, studies have demonstrated inconsistent findings and there exist variations in design.

Aim: To measure the association between medication use and MC.

Methods: Patients who underwent a colonoscopy over a 10-year period at two academic medical centres (Columbia University Medical Centre and Mayo Clinic) were identified. Cases were patients with biopsy-proven MC and controls were patients who underwent colonoscopy for evaluation of diarrhoea with biopsies negative for MC. Cases were matched by age, gender and calendar period with up to two controls. Demographics, medication use, smoking history and coeliac disease status were collected. Conditional logistic regression was used with and without adjustment for smoking.

Results: A total of 344 patients with MC were matched to 668 controls. After adjusting for smoking, there was an inverse association between MC and use of proton pump inhibitors (PPIs) (OR 0.64; 95% CI 0.47-0.87), H2 blockers (OR 0.46; 95% CI 0.24-0.88) and oral diabetes medications (OR 0.47; 95% CI 0.27-0.81). There was a positive association with nonsteroidal anti-inflammatory drug (NSAID) use and MC (OR 1.63; 95% CI 1.12-2.38).

Conclusions: NSAID use was associated with MC, while use of PPIs, H2 blockers and oral diabetes medications were inversely related to MC. Our use of a control group with diarrhoea, as opposed to healthy controls, may have contributed to these inverse associations. Future studies of drug-induced microscopic colitis should include control groups with diarrhoea, and not only healthy controls.
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http://dx.doi.org/10.1111/apt.16363DOI Listing
June 2021

Novel risk factors and outcomes in inflammatory bowel disease patients with infection.

Therap Adv Gastroenterol 2021 12;14:1756284821997792. Epub 2021 Mar 12.

Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.

Background: Patients with inflammatory bowel disease (IBD) are at significantly increased risk for infection (CDI) with an increased risk of adverse outcomes including increased in-hospital mortality, IBD treatment failure, re-hospitalization, and high CDI recurrence rates. The existing literature on predictors of these adverse outcomes is limited. We evaluated four potentially modifiable novel risk factors [body mass index (BMI), statin use, opioid use, and antidepressant use] on CDI risk and adverse outcomes in these patients.

Methods: Using a retrospective design, variables were abstracted from records for patients with IBD and CDI from 2008 to 2013. Statistical analysis comprised descriptive statistics and univariate and multivariate logistic regression analyses.

Results: There were 137 patients with IBD and CDI included in this study. On multivariate analysis controlling for age, 43% of patients in the overweight BMI category had severe or severe, complicated CDI, compared with 22% of patients in the underweight/normal BMI [odds ratio (OR) 2.85,  = 0.02] and 19% in the obese category (OR 3.95,  = 0.04). Statin use was associated with severe or severe, complicated CDI when controlling for age and BMI (OR 5.66,  = 0.01). There was no association between statin use and IBD exacerbations following CDI. Opioid and antidepressant use were not associated with disease severity or frequency of IBD exacerbations following CDI.

Conclusions: An overweight BMI and statin use were associated with severe or severe, complicated CDI in IBD patients. Further studies are needed to better understand how these factors impact management of patients with IBD to improve clinical outcomes and potentially reduce the risk of complications from CDI.
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http://dx.doi.org/10.1177/1756284821997792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958162PMC
March 2021

Efficacy of oral vancomycin prophylaxis for prevention of infection: a systematic review and meta-analysis.

Therap Adv Gastroenterol 2021 23;14:1756284821994046. Epub 2021 Feb 23.

Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

Background: Prevention of recurrent infection (CDI) is a challenge in clinical practice, particularly in patients who need systemic antimicrobial therapy. We aimed to evaluate the role of oral vancomycin prophylaxis (OVP) in prevention of primary or future CDI in patients on systemic antimicrobial therapy.

Methods: A systematic search of MEDLINE, Embase, and Web of Science was performed from 2000 to January 2020. We included case-control or cohort studies that included patients on systemic antimicrobial therapy who did or did not receive oral vancomycin prophylaxis (OVP) and were evaluated for development of CDI. Odds ratio (OR) estimates with 95% confidence intervals (CI) were calculated.

Results: Four studies including 1352 patients evaluated OVP for primary CDI prevention, with CDI occurring in 29/402 patients on OVP (7.4%) compared with 10.4% (99/950) without OVP. Meta-analysis revealed no significant decrease in risk of CDI in patients who received OVP (OR, 0.18; 95% CI, 0.03-1.03;  = 0.06). There was significant heterogeneity with  = 76%. Ten studies including 9258 patients evaluated OVP for secondary CDI prevention. Future CDI occurred in 91/713 patients on OVP (13.3%) compared with 21.9% (1875/8545) who did not receive OVP. Meta-analysis revealed a statistically significant decreased risk of future CDI (OR, 0.34; 95% CI, 0.20-0.59;  < 0.00001). Significant heterogeneity was seen with  = 59%.

Discussion: Based on observational data, OVP appears to decrease the risk of future CDI in patients with prior CDI who require systemic antimicrobial therapy. However, OVP was not effective for primary prevention of CDI.
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http://dx.doi.org/10.1177/1756284821994046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905721PMC
February 2021

An expert consensus to standardise clinical, endoscopic and histologic items and inclusion and outcome criteria for evaluation of pouchitis disease activity in clinical trials.

Aliment Pharmacol Ther 2021 05 18;53(10):1108-1117. Epub 2021 Mar 18.

London, ON, Canada.

Background: Pouchitis is a condition with large unmet medical needs and no approved therapies. Lack of validated instruments to measure disease activity and treatment response is a major barrier to drug development.

Aim: To conduct a modified RAND/University of California Los Angeles appropriateness process to produce a standardised assessment of pouchitis disease activity in clinical trials.

Methods: A list of 164 items generated upon a systematic review and expert opinion were rated based on a 9-point scale (appropriate, uncertain and inappropriate), by a panel including 16 gastroenterologists, surgeons and histopathologists.

Results: Items rated as appropriate to evaluate in pouchitis clinical trials were: (a) clinical: stool frequency and faecal urgency; (b) endoscopic: primary assessment in the pouch body according to the percentage of affected area (<50%, 50%-75% and >75%), evaluation of the presence of ulcers/erosions according to size (erosions <5 mm, ulcers ≥5 mm to 2 cm and large ulcers >2 cm) and ulcerated area (<10%, 10%-30% and >30%); (c) histologic: two biopsies from each segment, from the ulcer's edge when present, or endoscopically normal areas, assessment of lamina propria chronic inflammation, epithelial and lamina propria neutrophils, epithelial damage, erosions and ulcers; and (d) clinical trial inclusion/outcome criteria: minimum histologic disease activity for inclusion, a primary endpoint based on stool frequency and assessment of clinical, endoscopic and histologic response and remission. The overall majority of items surveyed (100/164) were rated 'uncertain'.

Conclusion: We conducted a RAND/UCLA appropriateness process to help inform measurement of pouchitis disease activity within clinical trials and foster the development of novel therapies.
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http://dx.doi.org/10.1111/apt.16328DOI Listing
May 2021

Long-term Safety of Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection.

Gastroenterology 2021 05 11;160(6):1961-1969.e3. Epub 2021 Jan 11.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: Fecal microbiota transplantation (FMT) is highly effective for treating recurrent Clostridioides difficile infection (CDI), with emerging data on intermediate and long-term safety.

Methods: A prospective survey-based study was conducted (September 2012-June 2018) in patients undergoing FMT for recurrent CDI. Data on demographics and comorbidities were abstracted from medical records. Patients were contacted at 1 week, 1 month, 6 months, 1 year (short-term), and ≥2 years post-FMT (long-term). Symptoms and new medical diagnoses were recorded at each time point. Data were weighted to account for survey nonresponse bias. Multivariate logistic regression models for adverse events were built using age (per 10-year increment), sex, time of survey, and comorbidities. P < .05 was considered statistically significant.

Results: Overall, 609 patients underwent FMT; median age was 56 years (range, 18-94), 64.8% were women, 22.8% had inflammatory bowel disease (IBD). At short-term follow-up (n = 609), >60% of patients had diarrhea and 19%-33% had constipation. At 1 year, 9.5% reported additional CDI episodes. On multivariable analysis, patients with IBD, dialysis-dependent kidney disease, and multiple FMTs had higher risk of diarrhea; risk of constipation was higher in women and lower in IBD (all P < .05). For long-term follow-up (n = 447), median time of follow-up was 3.7 years (range, 2.0-6.8). Overall, 73 new diagnoses were reported: 13% gastrointestinal, 10% weight gain, 11.8% new infections (all deemed unrelated to FMT). Median time to infections was 29 months (range, 0-73) post-FMT.

Conclusion: FMT appears safe with low risk of transmission of infections. Several new diagnoses were reported, which should be explored in future studies.
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http://dx.doi.org/10.1053/j.gastro.2021.01.010DOI Listing
May 2021

Durability Of Response To Fecal Microbiota Transplantation After Exposure to Risk Factors for Recurrence In Patients With Clostridioides difficile Infection.

Clin Infect Dis 2020 Sep 25. Epub 2020 Sep 25.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Background: Fecal microbiota transplantation (FMT) is highly effective for preventing recurrent Clostridioides difficile infection (CDI). Durability (no recurrence despite additional risk factor exposure) of FMT protection is largely unknown. We studied the durability of FMT in patients with recurrent CDI.

Methods: A retrospective study of adults undergoing FMT for recurrent CDI was conducted. Data collected included demographics, CDI risk factors (comorbidities, healthcare exposure, systemic non-CDI antibiotic use, acid suppressant medications) and future CDI episodes. Durable response to FMT was defined as lack of CDI episodes within 1 year post-FMT despite risk factor exposure. Descriptive statistics, univariate and multivariable Cox proportional hazards regression were used as applicable. Two tailed p<0.05 was considered statistically significant.

Results: Overall 460 patients were included [median age 57 (18-94) years, 65.2% female]. Comorbidities included chronic liver disease, 12.8% (n=59), cancer, 11.7% (n=54), chronic kidney disease, 3.9% (n=18) and inflammatory bowel disease, 21.9% (n=101). Overall, 31.3% (n=144) received antibiotics, 21.7% (n=100) received acid suppressants, 76.8% (n=350) had healthcare exposure after FMT. Of 374 patients with risk factor exposure, 78.1% [95% confidence interval (CI) 72.7%-84.0%] had durable response to FMT at one year. On multivariable analysis, antibiotic use was independently associated with decreased durability of FMT [hazard ratio 0.27 (95% CI, 0.15-0.49), p<0.001].

Conclusion: Majority of patients had a durable response to FMT despite exposure to CDI risk factors. Antibiotic exposure after FMT independently predicted loss of durability of FMT. Larger studies are needed to define predictors of durable response in patients with and without exposure to antibiotics.
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http://dx.doi.org/10.1093/cid/ciaa1457DOI Listing
September 2020

RBX7455, a Room Temperature-Stable, Orally-Administered Investigational Live Biotherapeutic, is Safe, Effective, and Shifts Patients' Microbiomes in a Phase 1 Study for Recurrent Clostridioides difficile Infections.

Clin Infect Dis 2020 Sep 23. Epub 2020 Sep 23.

Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN, USA.

Background: Recurrent Clostridioides difficile infections (rCDI) are a global public health threat. To reduce rCDI, microbiota-restoring therapies are needed, particularly standardized, easy-to-administer formulations.

Methods: This Phase I open-label trial assessed the safety, efficacy in preventing rCDI recurrence, and intestinal microbiome effects of RBX7455, a room temperature-stable, orally administered investigational live biotherapeutic. Adult participants with one or more prior episodes of rCDI received: four RBX7455 capsules twice daily for four days (Group 1); four RBX7455 capsules twice daily for two days (Group 2); or two RBX7455 capsules twice daily for two days (Group 3). For all groups, the first dose was administered in clinic, with remaining doses self-administered at home. Adverse events were monitored during and for 6 months after treatment. Treatment success was defined as rCDI prevention through 8 weeks after treatment. Participants' microbiome composition was assessed prior to and for 6 months after treatment.

Results: Nine of 10 Group 1 patients (90%), 8 of 10 Group 2 patients (80%), and 10 of 10 Group 3 patients (100%) were recurrence-free at the 8-week endpoint with durability to 6 months. Seventy-five treatment-emergent adverse events were observed in 27 participants with no serious investigational product-related events. Prior to treatment, participants' microbiomes were dissimilar from the RBX7455 composition with decreased Bacteroidia- and Clostridia-class bacteria, whereas after treatment, responders' microbiomes showed increased Bacteroidia and Clostridia.

Conclusions: Three dosing regimens of RBX7455 were safe and effective at preventing rCDI. Responders' microbiomes converged toward the composition of RBX7455. These results support its continued clinical evaluation.

Clinical Trials Registration: NCT02981316.
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http://dx.doi.org/10.1093/cid/ciaa1430DOI Listing
September 2020

Incidence of infection in peripartum women: a retrospective cohort study.

Therap Adv Gastroenterol 2020 27;13:1756284820942621. Epub 2020 Jul 27.

Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.

Background: The incidence of infection (CDI) is increasing in the general population. Data on the epidemiology of CDI in peripartum women - a highly vulnerable patient population - is scarce. The objective of this study was to report the incidence of CDI in peripartum women.

Methods: A single-center retrospective cohort study was conducted in peripartum women from 1997 to 2017. Peripartum CDI was defined as definite CDI (watery diarrhea for >24 h with positive stool assay) during pregnancy, or within 6 weeks postpartum. Incidence was reported per 100,000 pregnancies and time trends in incidence were analyzed using Poisson regression. Analyses were done separately for time trends before and after 2007, when CDI testing strategy changed to polymerase chain reaction.

Results: From 1997 to 2017, 80 patients with peripartum CDI (47 during pregnancy, 33 postpartum) out of 125,683 pregnancies (0.064%) were identified. Incidence of CDI increased 3.4 fold (95% confidence interval 1.5-7.4,  = 0.005) over the 21 year period. Time trends were evident after ( = 0.054), but not before 2007 ( = 0.97).

Conclusion: Incidence of CDI in peripartum women increased over the 21 year study period. The rise in incidence is concerning, and calls for heightened surveillance for CDI in this highly vulnerable population.
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http://dx.doi.org/10.1177/1756284820942621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385813PMC
July 2020

Predictors and Management of Failed Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection.

J Clin Gastroenterol 2021 07;55(6):542-547

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

Background And Goals: Clostridioides difficile infection (CDI) recurs in 10% to 15% after fecal microbiota transplantation (FMT). We identify predictors, and describe management and outcome of patients with recurrent CDI after FMT in a predominantly outpatient cohort.

Methods: A nested case-control study of patients undergoing FMT for recurrent CDI from August 2012 to January 2017 was performed. FMT failure was defined as recurrent diarrhea with positive C. difficile stool test during follow-up (≥2 mo). Controls (patients without FMT failures) were matched to cases 1:1 for sex and timing of FMT±1 month.

Results: Overall, 522 patients underwent FMT; 70 [13.4%; median age 53.8 years (range, 18 to 89 y), 54.3% females] recurred within a median 5.6 months (range, 0.2 to 34.9 mo). Number of prior CDI episodes, prior CDI treatment, and prior CDI-related hospitalizations were similar in cases and controls. Systemic antibiotics after FMT (54.3% vs. 21.4%, P<0.0001), inflammatory bowel disease (IBD) (34.3% vs. 15.7%, P=0.01), pseudomembranes at FMT (4.3% vs. 0%, P=0.03), and poor bowel preparation (68.5% vs. 31.4%, P=0.01) were associated with FMT failure. On multivariate analysis, IBD [odds ratio (OR) 4.34; 95% confidence interval (CI), 1.24-15.15], systemic antibiotics (OR 7.39; 95% CI, 3.02-18.07), and poor bowel preparation (OR 3.84; 95% CI, 1.59-9.28) predicted FMT failure with an area under the curve of 0.78. Among FMT failures, 37 (52.8%) were managed with antibiotics, 32 (45.7%) with repeat FMT after antibiotics and 1 with colectomy.

Conclusions: Use of systemic antibiotics, IBD, and poor bowel preparation predict FMT failure. Patients with FMT failure can be managed with antibiotics and/or repeat FMT.
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http://dx.doi.org/10.1097/MCG.0000000000001398DOI Listing
July 2021

A 1-Year Cross-sectional Inflammatory Bowel Disease Surveillance Colonoscopy Cohort Comparing High-definition White Light Endoscopy and Chromoendoscopy.

Inflamm Bowel Dis 2021 04;27(5):594-602

Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Minnesota, USA.

Background: We sought to compare the dysplasia detection rate of high-definition white light endoscopy (HDWLE) with that of chromoendoscopy in patients with long-standing inflammatory bowel disease (IBD).

Methods: This is a retrospective observational cohort of patients with IBD who underwent surveillance colonoscopy between October 1, 2016 and September 30, 2017. We assessed the association between dysplasia detection and multiple variables.

Results: A total of 808 unique colonoscopies were performed, of which 150 (18.6%) included chromoendoscopy. Primary sclerosing cholangitis was a comorbid diagnosis in 24.5% of patients. The performing endoscopist was an IBD specialist with 37.1% of patients and had >10 years' experience with 64.9% of patients. Prior dysplasia had been seen in 245 (30.3%) patients: 102 (68.0%) and 143 (22.0%) among patients who had chromoendoscopy and HDWLE, respectively. Dysplasia in polyps was found in 129 procedures (15.1%). Among patients who had chromoendoscopy and HDWLE, polypoid dysplasia was identified in 50 (33.0%) and 79 (12.0%) patients, respectively, P < 0.01. Dysplasia in random biopsies was found in 39 patients (4.8%): 15 (10%) who had chromoendoscopy and 24 (3.6%) who had HDWLE (P < 0.001). On multivariate analysis, patient and disease characteristics significantly associated with an increased odds for polypoid dysplasia included older age at diagnosis (odds ratio [OR] = 1.3 per 10 years; 95% confidence interval [CI], 1.07-1.60), having an IBD physician endoscopist (OR = 1.6; 95% CI, 1.01-2.67), having an endoscopist with less than 10 years' experience (OR = 1.8; 95% CI (1.16-2.89), and prior random dysplasia (OR = 4.2; 95% CI (1.93-9.17). Concomitant primary sclerosing cholangitis was significantly associated with random dysplasia (OR = 2.3; 95% CI, 1.02-5.07). After multivariate analysis adjusting for these variables, chromoendoscopy was no more likely to identify dysplasia than was HDWLE.

Conclusions: Chromoendoscopy and HDWLE had a similar diagnostic yield for dysplasia detection in patients with chronic IBD-colitis after adjusting for multiple known risk factors.
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http://dx.doi.org/10.1093/ibd/izaa146DOI Listing
April 2021

Collagenous Colitis Is Associated With HLA Signature and Shares Genetic Risks With Other Immune-Mediated Diseases.

Gastroenterology 2020 08 1;159(2):549-561.e8. Epub 2020 May 1.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.

Background & Aims: Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease.

Methods: DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells.

Results: Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases.

Conclusions: In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.
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http://dx.doi.org/10.1053/j.gastro.2020.04.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483815PMC
August 2020

SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial.

Clin Infect Dis 2021 06;72(12):2132-2140

Seres Therapeutics, Cambridge, Massachusetts, USA.

Background: Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs.

Methods: In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile-positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed.

Results: 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11-2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity.

Conclusions: Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial.

Clinical Trials Registration: NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.
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http://dx.doi.org/10.1093/cid/ciaa387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204772PMC
June 2021

Update on Treatment of Clostridioides difficile Infection.

Mayo Clin Proc 2020 04;95(4):758-769

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. Electronic address:

Clostridioides difficile infection (CDI) is the leading cause of health care-associated infections in the United States. The increasing incidence and recurrence rates of CDI together with its associated morbidity and mortality are great concerns. Newer treatment methods, such as narrow-spectrum antibiotics, monoclonal antibodies, and microbial replacement therapies, are being developed and implemented. We searched PubMed to identify published literature from 2010 to 2018 using the following keywords: Clostridium difficile, treatment, and therapy. Cited references were also used to identify relevant literature. This review focuses on the current standard of therapy and emerging therapies for CDI and summarizes the updated guidelines on treatment of CDI.
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http://dx.doi.org/10.1016/j.mayocp.2019.08.006DOI Listing
April 2020

Combination Biologic Therapy in Inflammatory Bowel Disease: Experience From a Tertiary Care Center.

Clin Gastroenterol Hepatol 2021 03 14;19(3):616-617. Epub 2020 Feb 14.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

The global incidence of inflammatory bowel disease (IBD) has increased considerably during the past few decades. IBDs, composed of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by heterogeneous presentation and widely variable clinical course. The therapeutic goals are to induce and maintain remission. Despite the current treatments available, many patients do not achieve this goal.
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http://dx.doi.org/10.1016/j.cgh.2020.02.017DOI Listing
March 2021

Response to 'Comments on the published systematic review and meta-analysis on the increasing antibiotic resistance in Clostridioides difficile' by Kouhsari et al.

Anaerobe 2020 02 20;61:102148. Epub 2020 Jan 20.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA. Electronic address:

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http://dx.doi.org/10.1016/j.anaerobe.2020.102148DOI Listing
February 2020
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