Why Stool Hoarding Might Be A Good Idea

SK Hourigan et al. JPGN 2021; 73: 430-432. Updates and Challenges in Fecal Microbiota Transplantation for Clostridioides difficile Infection in Children

This good update provides a lot of useful information regarding fecal microbiota transplantation (FMT) and a word of caution regarding its future availability.

Key points regarding FMT:

  • Long-term safety remains unknown. FMT may lead to susceptibility to chronic inflammatory, allergic, and autoimmune diseases. “FMT has been associated with durable transmission of pro-carcinogenic bacteria from adult donors to pediatric recipients…although the long-term consequences…are unknown.”
  • Due to transfer of extended spectrum beta-lactamase (ESBL) E coli to 2 immunocompromised adult recipients, further screening of FMT was implemented.
  • Though there is no published evidence of SARS-CoV-2 fecal transmission, the FDA “advised additional precautions and testing in March 2020; “however, there are no molecular tests with stool…which have received emergency use authorization.” Hence, most FMT programs were on hold as of January 2021.
  • After 2021, OpenBiome, whose product was recently available again, is expected to stop distribution of FMT donor product due to increased costs of screening and the “promising biotherapeutics” that are in phase III trials.
  • Biotherapeutic is “loosely defined as drug therapy products where the active substance is extracted from a biological specimen.” The new products are likely to have “increased standardization, safety and practicality.”
  • The problem in pediatrics: none of these biotherapeutic products have started trials in children. This will lead to treatment problems. Even if one wanted to set up donor-directed FMT, it will be difficult to complete all of the screening recommended by the FDA. It could lead to self-administration by families with uncertain risks.

My take: My first reaction to this article: ‘Oh crap!’ It is sad and ironic that I will miss having available commercial stool for FMT.

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Secondary Prophylaxis of Clostridiodes difficile Infection

H Bao et al. Pediatrics 2021; 148: e2020031807. Oral Vancomycin as Secondary Prophylaxis for Clostridioides difficile Infection. Thanks to Ben Gold for sharing this reference.

Methods: A multicampus, retrospective cohort evaluation was conducted among patients aged ≤18 years with any history of clinical CDI and receiving systemic antibiotics in a subsequent encounter from 2013–2019. This study identified 30 and 44 patients received oral vancomycin prophylaxis (OVP) and no OVP, respectively. Eligible patients had to be >12 months of age and having at 3 unformed stools everyday.

OVP dosing: “vancomycin doses of 10 mg/kg (up to 125 mg per dose) every 12 hours during concomitant antibiotic use. OVP duration was intended to continue while on systemic antimicrobial agents and for 5 days after completion of antimicrobial agents (extended prophylaxis tail), but practice varied, and duration was ultimately left to the discretion of the provider.”

Key finding:

The incidence of CDI recurrence within 8 weeks of antibiotic exposure was significantly lower in patients who received OVP (3% vs 25%P = .02) despite this group having notably more risk factors for recurrence.   After adjustment in a multivariable analysis, secondary OVP was associated with less risk of recurrence (odds ratio, 0.10; 95% confidence interval, 0.01–0.86; P = .04).

This study is in agreement with studies in adults (Brown CC, et al. Oral Vancomycin for Secondary Prophylaxis of Clostridium difficile Infection. Ann Pharmacother. 2019 Apr;53(4):396-401). In this review, the authors state: “Variable dosing regimens and lack of safety data are limitations.. clinicians can consider vancomycin 125 mg orally once or twice daily in high-risk patients receiving broad-spectrum antibacterial agents.”

My take: In patients at high risk of recurrent CDI, OVP should be considered as secondary prophylaxis when receiving systemic antibiotics.

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Looking at the Mycobiome to Distinguish Clostridium difficile Infection vs. Carriage

Y Cao et al. Gastroenterol 2021; 160: 2328-2339. Fecal Mycobiota Combined With Host Immune Factors Distinguish Clostridioides difficile Infection From Asymptomatic Carriage

Key findings:

  • The ratio of Ascomycota to Basidiomycota was dramatically higher in patients with CDI than in Carrier and Control (P < .05).
  • Using 4 fungal operational taxonomic units combined with 6 host immune markers in the random forest classifier can achieve very high performance (area under the curve ∼92.38%) in distinguishing patients with CDI from Carrier.

My take: It is interesting that fecal fungal diversity (mycobiome), in addition to bacterial diversity, is reduced in those with Clostridium difficile infection (CDI) compared to both control groups and those with Clostridium difficile asymptomatic carriage.

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Long-term Safety of Fecal Microbiota Transplantations

S Saha et al. Gastroenterol 2021; 160: 1961-1969. Full text PDF: Long-term Safety of Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection

In this prospective study (2012-2018) with 609 patients (median age 56 years), the authors studied long-term outcomes. Key findings:

  • At 1 year, 9.5% reported additional CDI episodes. Diarrhea occured in more than half of all patients, although it lasted for than a week in most patients.
  • Among 477 with long-term data, 188 patients post-FMT developed new medical conditions/symptoms.
  • Weight gain was reported by 46 patients (10.3%) post-FMT. In these patients, the median weight gained was 30 pounds (range, 10–70). Of these patients, 11 (23%) had
    preexisting obesity.
  • Approximately 3% of patients each reported new-onset diabetes mellitus and dyslipidemia,
    whereas 2.3% reported thyroid disease.
  • Gastrointestinal symptoms were the second most frequently reported (13.4%). New-onset IBS was reported by 4%, IBD by 0.3%, chronic diarrhea by 5.0%, and chronic constipation by 1.6% of patients.
  • Serious infections were reported by 11.8% of patients: CDI in 5.7%, Pneumonia in 4.5%, UTI in 1.8% and Sepsis in 1.2%. Median time to the infections was 29 months (range, 0–73) following FMT; only 1 patient reported an infection (CDI) within the first month after FMT.
  • No deaths were considered related to FMT
  • Limitation: no control group

My take (borrowed from authors): “FMT appears safe and effective, both in the
short-term and long-term. Several new medical conditions were reported post-FMT, in particular, weight gain and IBS.”

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ACG Clostridium Difficile Guidelines Plus One

CR Kelly et al. Am J Gastroenterol 2021;00:1–24. https://doi.org/10.14309/ajg.0000000000001278; published online May 18, 2021. Full text PDF: ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections

Key points:

  • Guideline recommends AGAINST using probiotics for prevention of C difficile infection (CDI)
  • Guideline cautions AGAINST testing individuals at low risk for CDI (eg. not having diarrhea)
  • Guideline recommends either vancomycin or fidaxomicin (lower CDI recurrence) for all cases of CDI and consideration of metronidazole for nonsevere cases. Fidaxomicin is recommended for CDI recurrence after vancomycin or metronidazole.
  • Guideline recommends combination of highly sensitive test and highly specific test for diagnosis of CDI. “CDI-related complications are rare in NAAT-positive, toxin EIA-negative patients, who, even when untreated, may have clinical courses similar to those without CDI…If both are positive, the diagnosis of CDI can be made reliably. If both are negative, CDI is unlikely. Discordant results when NAAT or GDH is positive and toxin EIA is negative require clinical evaluation and consideration of the possibility of colonization or that the patient has CDI but toxin levels are below the limits of detection (see below).

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Also, I recommend this article in the NY Times about a liver/intestinal transplant surgeon (who has taken care of some of our patients): ‘I Had Never Faced the Reality of Death’: A Surgeon Becomes a Patient

Why It Is Still A Bad Idea To Test Asymptomatic Patients For Clostridium Difficile

JM Parnell et al. JPGN 2021; 72: 378-383. Two-step Testing for Clostridioides Difficile is Inadequate in Differentiating Infection From Colonization in Children

In this prospective study, the authors enrolled asymptomatic pediatric patients (n=225) and compared C diff testing results with symptomatic patients (n=41) with positive nucleic-acid amplification-based testing (NAAT).

Key findings:

  • Of the 225 asymptomatic children enrolled in the study, 47 (21%) were colonized with C. difficile including 9/59 (15.5%) with cancer, 30/92 (32.6%) with CF, and 8/74 (10.8%) with IBD. 
  • Overall, “use of a multistep testing algorithm with NAAT followed by EIA failed to differentiate symptomatic CDI from asymptomatic colonization in our pediatric cohort.” When symptomatic and colonized children were compared, neither EIA (enzyme immunoassay) positivity (44% vs 26%, P = 0.07) nor CCNA (functional cell cytotoxicity neutralization assay) positivity (49% vs 45%, P = 0.70) differed significantly

My take: Don’t test children who are asymptomatic for Clostridium difficile. Even in children with symptoms, C diff positivity could reflect colonization and symptoms could be due to other etiologies.

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“Real-world” Efficacy for Fecal Microbiota Transplantation

CR Kelly et al. Gastroenterol 2020; doi.org/10.1053/j.gastro.2020.09.038 (in press). Fecal Microbiota Transplantation Is Highly Effective in Real-World Practice: Initial Results From the FMT National Registry

Background: “The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers.” n=259 with 222 who completed short-term follow-up.

Key findings:

  • All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank).
  • 90% (n=200) were considered cured at one month. Of these, 197 (98%) received only 1 FMT.
  • Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence.
  • Safety:  Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%). Milder adverse events were noted in 45% with symptoms including diarrhea, abdominal pain, bloating or constipation.

My take: Overall, the findings from this prospective registry confirm that FMT works fairly well for CDI. Long-term follow-up will provide more answers on the safety of FMT.

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AGA Practice Guidelines: Probiotics NOT Helpful for Most GI Conditions

Here is a link to the EPUB draft of AGA clinical report (G Su et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2020.05.059): AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders

Here is a link to the pre-draft technical review by GA Preidis et al. Gastroenterology DOI: https://doi.org/10.1053/j.gastro.2020.05.060 AGA Technical Review on the Role of Probiotics in the Management of Gastrointestinal Disorders

  • The report recommends NOT using probiotics outside of clinical trials for irritable bowel syndrome, Clostridium difficile infection treatment, Crohn’s disease, and gastroenteritis.
  • It recommends a specific probiotic for pouchitis and for prevention of necrotizing enterocolitis in preterm infants <37 weeks and 3 probiotics for patients who are receiving antibiotics (to prevent Clostridium difficile infection)

CNN summary: Probiotics don’t do much for most people’s gut health despite the hype, review finds

“While our guideline does highlight a few use cases for probiotics, it more importantly underscores that the public’s assumptions about the benefits of probiotics are not well-founded,” said Dr. Grace L. Su, a professor of medicine and chief of gastroenterology at the University of Michigan, Ann Arbor, in a news statement. She was the chair of the panel that issued the new guidance….

“The industry is largely unregulated and marketing of product is often geared directly at consumers without providing direct and consistent proof of effectiveness,” said the new guidelines. “This has led to widespread use of probiotics with confusing evidence for clinical efficacy,” it said…

“Not all probiotics are created equal. Some probiotic strains and mixtures are very effective for some types of diseases and should not be overlooked due to studies that lump all probiotics together as one”

My take: Probiotics are overhyped and underperform for most conditions. This report suggests that most people should NOT be taking probiotics.

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Great Issue: We Need More Negative Studies (Published)

A recent ACG “Negative Issue” had some terrific articles –thanks to Ben Gold for sharing his issue.

Here are a few of the studies:

  1. Buspirone had similar efficacy as placebo in a randomized clinical trial for childhood functional abdominal pain, (n=117)  Full text: Comparison of the Efficacy of Buspirone and Placebo in Childhood Functional Abdominal Pain Key finding: Treatment response rates for buspirone and placebo were 58.3% and 59.6% at week 4 (P = 0.902) and 68.1% and 71.1% at week 12 (P = 0.753), respectively.
  2. IBS does not increase mortality in a nationwide cohort study (>300,000 in study)  Full text: Mortality Risk in Irritable Bowel Syndrome Key finding: After adjustment for confounders, IBS was not linked to mortality (HR = 0.96; 95% CI = 0.92–1.00) …and patients with IBS not undergoing a colorectal biopsy were at no increased risk of death (HR = 1.02; 95% CI = 0.99–1.06).
  3. Mongerson was not effective for active Crohn’s disease in a large phase 3 study, n=701 Full text: Mongersen (GED-0301) for Active Crohn’s Disease Key finding: The primary endpoint, clinical remission achievement (CD Activity Index score <150) at week 12, was attained in 22.8% of patients on GED-0301 vs 25% on placebo (P = 0.6210). At study termination, proportions of patients achieving clinical remission at week 52 were similar among individual GED-0301 groups and placebo.
  4. Treatment of H pylori did not increase the risk of C difficile infection (retrospective study)  Full text: Treatment of Helicobacter pylori & Clostridium difficile  Key finding: Of these 38,535 patients with H pylori based on endoscopic pathology, urea breath testing, or stool antigen, 284 (0.74%) had subsequent CDI. Those who developed CDI were less likely to have received treatment for HP within the VHA (66.2% vs 74.8%, P < 0.001)
  5. Percutaneous liver biospy was not safer when done by experienced clinician compared to a fellow, n=212 biopsies  Full text: Major Complications of Pediatric Percutaneous Liver Biopsy Do Not Differ Among Physicians With Different Degrees of Training  Key finding: No significant differences were found between groups (fellows vs staff) regarding number of punctures (median of 1.7 for both), nonrepresentative biopsies (4.2% vs 2.6%), and hemoglobin drop (median of 0.7 vs 0.5 g/L).  Interestingly, in the discussion, the authors assert: “previous studies do not support the conclusion that ultrasound-guided biopsies are superior in terms of safety or adequacy when compared with the use of ultrasound to mark the puncture” (this is based on a study referenced from 2007:  J Gastroenterol Hepatol 2007;22(9):1490–3.)  However, given that severe complications from liver biopsy are infrequent, this current study may be underpowered to detect a small difference between experienced clinicians and fellows.

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It’s come to this:  Link: YouTube: Dirty Dancing Remake -Safest with a Lamp (this link is for Bernsie). 4 minute video.

Two Studies: 1. COVID-19 Transmissibility 2.Fecal Microbiota Transplantation in 372 Children

A study in Nature suggests that more than 40% of SARS-CoV-2 infections (COVID-19 viral infections) are spread in the presymptomatic stage: Temporal dynamics in viral shedding andtransmissibility of COVID-19 (Thanks to Steven Liu for this reference).

An excerpt:
We report temporal patterns of viral shedding in 94 patients with laboratory-confirmed COVID-19 and modeled COVID-19 infectiousness profiles from a separate sample of 77 infector–infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25–69%) of secondary cases were infected during the index cases’ presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home. Disease control measures should be adjusted to account for probable substantial presymptomatic transmission.

——————————-

A recent retrospective multi-center study (MR Nicholson et al. Clin Gastroenterol Hepatol 2020; 18: 612-9) provides data on fecal microbiota transplantation (FMT) for Clostridium difficile infection (CDI). Congratulations to one of my partners, Jeffery Lewis, who is one of the coauthors. This paper’s abstract is noted in a separate blog: Large Study Show FMT Efficacy/Safety in Children.

Though this is a pediatric study, the authors included patients up to 23 years.  335 of the patients had followup for at least 2 months following FMT.

Key findings:

  • 81% of patients had a successful outcome after a single FMT and 86.6% after single or repeated FMT
  • Higher success rates were associated with fresh donor stool (OR 2.66), FMT via colonoscopy (OR 2.41), and with not having a feeding tube (OR 2.08)
  • Though not reaching statistical significance, patients with inflammatory bowel disease had a high failure rate of 23% (26/111).  Short bowel syndrome patients had a 50% failure rate (5/10), solid organ transplant recipients had a 56% failure rate (5/9), and patients with feeding tubes had a 32% failure rate (21/65).
  • Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations; however, the majority were unrelated to FMT. Specific adverse reactions that were related or may have been included aspiration pneumonia on day of procedure (n=1), IBD flare/colectomy (n=5), and vomiting/dehydration (n=1)
  • Common adverse reactions included diarrhea, abdominal pain, and bloating. (These symptoms have been reported in up to 70% of adults following FMT.)

The authors note that a prior systematic review had indicated that delivery of FMT via colonoscopy was more successful in adults (95% vs 88%), though there are some additional risks with colonoscopy.

It is worth considering that the failure rate in some patients could be due to misdiagnosis, particularly in certain populations like patients with IBD and or organ transplant recipients.  In these populations, PCR assays may result in false-positive diagnosis and should be confirmed with an ELISA assay.   While eradication of CDI with FMT improves clinical symptoms and reduces the use of antibiotics the true benefit and risks will not be known for a long time.  Does FMT increase or reduce the risk of downstream infections, autoimmune disease, and metabolic syndrome?

My take: Many of the concerns with FMT can only be adequately addressed with prospective studies (with strict definitions of CDI) and longer followup.

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