“No Solid Conclusions” for Alternative/Complementary Therapies for Inflammatory Bowel Disease

In this clinical review (N Chande et al Inflamm Bowel Dis 2020; 26: 843-51) assess evidence from Cochrane reviews of four popular nontraditional treatments for inflammatory bowel disease (IBD):

  • Fecal Microbiota Transplantation (FMT)
  • Nutritional Therapies including Enteral Nutrition (EN)
  • Naltrexone for Crohn’s Disease (CD)
  • Cannabis for IBD

So what does the literature have to say about these treatments:

  • FMT: FMT for mild to moderate ulcerative colitis (UC) increased the proportion of patients achieving clinical remission. “However, the number of included studies was small and the quality of evidence was low.”  Other problems included uncertainty regarding serious adverse events and short duration of followup.
  • “As a result, no solid conclusions [the authors did not indicate this as a pun] can be drawn at this time.”

  • Nutritional Therapies: For remission in CD, “EN may be more effective than corticosteroids in children, although the opposite was true in adults.”
  • “Exclusion diets did not promote clinical remission or reduce clinical relapse in UC”
  • “The overall certainty of evidence in these studies were generally very low, largely due to sparse data.”

  • Naltrexone for Crohn’s Disease (CD): “The paucity of data makes it impossible to draw any firm conclusions about the effectiveness and safety” of low dose naltrexone.

  • Cannabis for IBD: “The risk of adverse events was significantly higher in cannabis-treated patients”…though these events were generally mild (eg. sleepiness, confusion, nausea).
  • “The results of these studies suggest that cannabis is not effective for the treatment of IBD”  This conclusion is limited by the small number of patients in prior studies.  Cannabis may be helpful as an adjunct for some symptoms though this “warrants further study.”

Related blog posts:

 

 

Not Curing Obesity with Fecal Microbiota Transplantation & More on Remdesivir

A recent pilot (n=22) double-blind study (JR Allegrett et al. Clin Gastroenterol Hepatol 2020; 18: 855-63) pours cold water on the idea that repopulating one’s microbiome would be helpful in treating obesity.

In this study, the authors examined obese patients without diabetes, nonalcoholic steatohepatitis, or metabolic syndrome.  In the treatment group, patients received FMT by capsules: 30 capsules at week 4 and then a maintenance dose of 12 capsules at week 8.  All FMT was derived from a single lean donor.

Key findings:

  • There were no significant changes in mean BMI at week 12 in either group.
  • Patients in the FMT group had sustained shifts in microbiomes associated with obesity toward those of the donor (P<.001).  In addition, bile acid profiles became more similar to the donor.

My take: Though this was a small study, it suggests that changing the microbiome by itself is likely insufficient to result in significant weight loss.

Related blog posts:

JH Beigel et al. NEJM DOI: 10.1056/NEJMoa2007764 (May 22, 2020): Full text: Remdesivir for the Treatment of Covid-19 — Preliminary Report

This was a a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement (n=1063).

Key findings:

  • Faster recovery for remdesivir recipients: 11 days vs 15 days
  • Lower mortality rate: 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70, 95% CI, 0.47 to 1.04) (mortality difference did not reach statistical significance)

 

 

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.

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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.

Related blog posts:

Island Ford, Sandy Springs

FMT Warning & “Get Your Butt in Gear” –Less Than 10% of Kids Meeting Guidelines for Healthy Movement

To lessen obesity, three health risk behaviors have been targeted:

  • Sedentary behavior -goal is to limit to 2 hours of screen time in 24 hours
  • Physical activity -goal is 1 hour (or more) of moderate to vigorous activity
  • Sleep duration -goal is 9-12 hours (ages 6-12 years) and 8-10 hours (13-18 years)

A recent study (X Zhu et al. J Pediatr 2020; 218: 204-9) shows that <10% of U.S. kids meet these goals.  The authors examined data (2016-17) from the National Survey of Children’s Health (NSCH) dataset (n=71,811)

Key findings:

  • 80.9% did NOT meet physical activity goal
  • 76.2% did meet screen time goal
  • 581% did meet sleep goal
  • However, only 9.4% met all 3 goals
  • Not meeting these ‘movement’ guidelines was associated with obesity, particularly in females (aOR 4.97 compared to aOR 3.99 for males)

My take: We are all made to be different shapes and sizes.  Nevertheless, we should strive for healthy behaviors and healthy eating which could improve outcomes.

More Details on Drug-Resistant E coli Transmitted by Fecal Microbiota Transplant

In June 2019, the FDA delivered a warning about the potential danger of transmitting drug-resistant E coli with fecal microbiota tranplantaion (FMT).  (FDA Warning for FMT)

A report on this issue has now been published: Z DeFilipp et al. NEJM 381: 2043-50, editorial M Blaser pgs 264-6.

The authors describe two patients, a 69 year-old with cirrhosis and a 73 year-old sp stem cell transplantation, who developed bacteremia due to transmission of a drug-resistant (extended-spectrum beta-lactamase [ESBL]) E coli following FMT which was delivered by oral capsules. The latter patient died from sepsis. The two patients had a genomicly-identical strain isolated that was also found in the donated aliquot.

In the commentary, a couple of important points:

  • “Up to now, the complications have been infrequent [from FMT], and for recurrent C difficile infection, the benefits of FMT clearly outweigh the risks; however, as the use of FMT is broadened and more compromised patients are treated, complications may be more frequently observed.”
  • “In the short term, improved and uniform screening of FMT material is needed to reduce the risks.”

My take: Both of these patients who became developed bacteremia were at risk for more severe infections.  However, we need to remain aware that severe complications can and do occur with FMT.  In context, though, there are risks of severe complications from routine use of antibiotics as well.

Frontenac Hotel, Quebec City

Only 3% Make It Through the Donor Screening Process for Fecal Microbiota Transplantation

A recent letter (Z Kassam et al. NEJM 2019; 381: 2070-2) describes the arduous process involved in being selected as a stool donor for fecal microbiota transplantation (FMT).

In a previous blog (2015), it appeared that 17% of donors were accepted for FMT: Rejected! Most Stool is Not Good Enough for FMT This current review of the donor program from a stool bank (OpenBiome) prospectively evaluated 15,317 donor candidates from 2014-2018.

Key finding:

  • Only 3% (n=386) made it through all the steps to become donors

Reasons for exclusion:

Stage 1: common reasons for exclusion:

  • geographical -living too far away to donate regularly
  • BMI >30
  • social history
  • travel history
  • not in age range

Stage 2: “failing” the 200-item clinical assessment –common reasons for exclusion:

  • lost to followup
  • allergic disorders/asthma
  • receiving medications/supplements
  • mental health concerns
  • infectious disease history
  • social history/sexual history/other reasons

Stage 3: “failing” the stool and nasal screening which included (in 2016) carbapenem-resistant Enterobacteriacea (CRE), extended-spectrum beta-lactamase-producing organisms (ESBL) and MRSA. –common reasons for exclusion:

  • lost to followup
  • infectious disorders (including C diff in 7 patients)

Stage 4: “failing” serological screening

  • lost to followup
  • abnormal LFTs, CBC or infection

Related blog posts:

Island Ford, Sandy Springs, GA

Large Study Shows FMT Efficacy/Safety in Children

Clinical Gastroenterol Hepatol 2019. In press: Efficacy of Fecal Microbiota Transplantation for Clostridium difficile Infection in Children Thanks to Ben Gold for this reference.

Abstract

Background & Aims

Fecal microbiota transplantation (FMT) is commonly used to treat Clostridium difficile infection (CDI). CDI is an increasing cause of diarrheal illness in pediatric patients, but the effects of FMT have not been well studied in children. We performed a multi-center retrospective cohort study of pediatric and young adult patients to evaluate the efficacy, safety, and factors associated with a successful FMT for the treatment of CDI.

Methods

We performed a retrospective study of 372 patients, 11 months to 23 years old, who underwent FMTs at 18 pediatric centers, from February 1, 2004 to February 28, 2017; 2-month outcome data were available from 335 patients. Successful FMT was defined as no recurrence of CDI in the 2 months following FMT. We performed stepwise logistic regression to identify factors associated with successful FMT.

Results

Of 335 patients who underwent FMT and were followed for 2 months or more, 271 (81%) had a successful outcome following a single FMT and 86.6% had a successful outcome following a first or repeated FMT. Patients who received FMT with fresh donor stool (odds ratio [OR], 2.66; 95% CI, 1.39–5.08), underwent FMT via colonoscopy (OR, 2.41; 95% CI, 1.26–4.61), did not have a feeding tube (OR, 2.08; 95% CI, 1.05–4.11), or had 1 less episode of CDI before FMT (OR, 1.20; 95% CI, 1.04–1.39) had increased odds for successful FMT. Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations.

Conclusion

Based on the findings from a large multi-center retrospective cohort, FMT is effective and safe for the treatment of CDI in children and young adults. Further studies are required to optimize the timing and method of FMT for pediatric patients—factors associated with success differ from those of adult patients.

Related blog posts:

Park Guell, Barcelona

Cost Effective Fecal Transplantation

A recent retrospective study (DE Brumbaugh et al. J Pediatr 2018; 194: 123-7) examined the effectiveness of intragastric fecal microbiota transplantation (FMT) for recurrent Clostridium difficile infection (CDI) in 42 children (47 FMTs).

Key findings:

  • 94% (16/17) success in otherwise healthy children
  • 75%  (9/12) success in medically complex children
  • 54% (7/13) success in inflammatory bowel disease.
  • Figure 2 describes cost: nasogastric FMT cost for hospital/professional charges was $1139 compared to $4998 for nasoduodenal FMT and $7767 for colonoscopy FMT

To understand the results better, one needs to look at their methods.  The authors defined CDI based on a positive fecal polymerase chain reaction (PCR) test.  All patients undergoing FMT had to have had >2 episodes of CDI.

The authors discuss the issue that asymptomatic Clostridium difficile carriage is common in IBD (“6 times that in healthy controls”) and the fact that true CDI can be difficult to ascertain as the relative contribution of IBD activity can be difficult to separate from CDI.  Interestingly, the authors did not comment on their use of PCR testing to establish infection.

As noted in a previous blog post (Overdiagnosis of Clostridium difficile with PCR assays), immunoassay testing for toxin is likely helpful in equivocal cases.  In an influential JAMA Intern Med study (JAMA Intern Med. 2015;175(11):1792-1801.  doi:10.1001/jamainternmed.2015.4114), virtually all CDI-related complications and deaths occurred in patients with positive toxin immunoassay test results. Patients with a positive molecular test result and a negative toxin immunoassay test result had outcomes that were comparable to patients without C difficile by either method.

Other useful points in this study:

  • The authors note that craniofacial anatomy may preclude NG placement in some patients (in some orogastric insertion could be an alternative)
  • Patients at high risk for GERD/aspiration along with general anesthesia patients are “not good candidates for FMT”
  • “If there is concern for undiagnosed IBD or other GI pathology, FMT via colonoscopy may be preferable” as FMT could be diagnostic and therapeutic.

My take: This study confirms the utility of intragastric FMT for recurrent CDI as a cost-effective option.  More careful examination of CDI in patients with IBD could result in determining which patients are most likely to benefit from FMT

Hoover Dam

 

Related blog posts:

FMT in the “Real World”

At DDW 2016, OpenBiome presented data (abstract Su1737) from 2,050 patients who received fecal microbiata transplants (FMT) in “the real world.”

Key findings:

  • Overall, 84% clinical cure rate with a single treatment
  • 85% of patients were treated with FMT via colonoscopy (250 mL) and 15% via nasal tube (50 mL). Nasal tube administration had a lower clinical cure rate of 77.9%, compared with 85.1% who had FMT via colonoscopy.

More information on this study: “Closet Thing to Miracle Cure”: Study Confirms Benefit of FMT in C difficile  Gastroenterology & Endoscopy News July 2016  This link also presents data on use of FMT in ulcerative colitis and the use of capsule FMT.

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Lymphonodular Hyperplasia2