“Real-world” Efficacy for Fecal Microbiota Transplantation

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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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Budesonide for Maintaining EoE Remission

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A Straumann et al. Gastroenterology 2020; Free Full Text Link: Budesonide Orodispersible Tablets Maintain Remission in a Randomized, Placebo-Controlled Trial of Patients With Eosinophilic Esophagitis

Methods: Two hundred and four adults with EoE in clinical and histologic remission, from 29 European study sites, were randomly assigned to groups given budesonide orodispersible tablet (BOT) 0.5 mg twice daily (n = 68), BOT 1.0 mg twice daily (n = 68), or placebo twice daily (n = 68) for up to 48 weeks

Key Findings:

  • At end of treatment, 73.5% of patients receiving BOT 0.5 mg twice daily and 75% receiving BOT 1.0 mg twice daily were in persistent remission compared with 4.4% of patients in the placebo group (P < .001 for both comparisons of BOT with placebo)
  • Four patients receiving BOT developed asymptomatic, low serum levels of cortisol. Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5 mg group and in 11.8% of patients in the BOT 1.0 mg group; all infections resolved with treatment

In the discussion, the authors state that “we recommend monitoring symptoms and signs of adrenal insufficiency when administrating topical-acting corticosteroids over prolonged time periods, in particular in children and when using higher dosages.”

My take (from discussion): “EoE requires a proper long-term anti-inflammatory therapy because, without active treatment, the vast majority of patients experience a relapse within the first 100 days after cessation of the medication.”

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A Path Forward for Microvillous Inclusion Disease?

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I Kaji et al. Gastroenterol 2020; 159: 1390-1405. Full free text: Lysophosphatidic Acid Increases Maturation of Brush Borders and SGLT1 Activity in MYO5B-deficient Mice, a Model of Microvillus Inclusion Disease

Key finding: Lysophosphatidic acid (LPA)partially restored the brush border height and the localization of SGLT1 and NHE3 in small intestine of MYO5B-knockout mice and enteroids. There are a number of high quality figures that illustrate these effects:

From Figure 1. Changes in  jejunal morphologies by MYO5B deletion and administration of LPA

Editorial, S Abtahi, JR Turner. Gastroenterol 2020; 159:1233-1235: Full free text: Exploiting Alternative Brush Border Trafficking Routes to Treat Microvillous Inclusion Disease

Background (from editorial):

  • Small bowel biopsies in MVID include enterocytes that have either sparse, blunted microvilli or lack microvilli completely. Large cytoplasmic inclusions with prominent luminal microvilli are, however, present along with increased numbers of subapical lysosomes and other small vesicles
  • Biochemically, brush border expression of the Na+-glucose cotransporter SGLT1 (Slc5a1), the N+-H+ exchanger NHE3 (Slc9a3), and aquaporin 7 are markedly decreased in patients with MVID
  • Myo5b knockout in mice induces histopathologic and clinical features of MVID, including villous blunting, growth failure, and increased stool water, that is, diarrhea
  • Previous studies have shown that NHE3 trafficking from the apical storage pool to the brush border could be triggered by lysophosphatidic acid (LPA)

Key points from editorial

  • Kaji et al treated adult Myo5bf/f x vil-CreERT2 mice with …oral or systemic LPA administration. Villous blunting, microvillous loss, and apical lysosomal expansion were substantially reversed after 4 days of systemic LPA treatment
  • Although the morphologic and physiologic responses induced by LPA are striking, the weight loss that began within 2 days of Myo5b knockout was not attenuated. Thus, despite being remarkably beneficial when assessed using laboratory assays, LPA has not yet been shown to be an effective therapeutic agent.

My take (borrowed from editorial): This study shows “there are multiple trafficking pathways to the brush border and that one of these can be exploited to overcome defects in another.”

Disease Activity, Not Medications, Linked to Neonatal Outcomes Among Women with IBD

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U Mahadevan at el. Gastroenterology; 2020: (in press) DOI:https://doi.org/10.1053/j.gastro.2020.11.038. Pregnancy and Neonatal Outcomes after Fetal Exposure To Biologics and Thiopurines among Women with Inflammatory Bowel Disease

Methods: Between 2007 and 2019, pregnant women with IBD were enrolled in a prospective, observational, multicenter study across the United States (PIANO registry). 

Key findings:

  • Exposure was to thiopurines (242), biologics (642) or both (227) versus unexposed (379)
  • Medication exposure did not increase the rate of congenital malformations, spontaneous abortions, preterm birth, LBW, and infections over the first year of life
  • Higher disease activity was associated with risk of spontaneous abortion (HR 3.41, 95% CI 1.51-7.69) and preterm birth with increased infant infection (OR 1.73, 95% CI 1.19-2.51)

My take: This study provides some reassurance that treatments for IBD are unlikely to affect neonatal outcomes; however, increased IBD activity does affect outcomes

Related blog post: IBD and Pregnancy

Expert Update on COVID-19 Pandemic and Vaccine Rollout

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Our hospital system has been arranging frequent staff meetings to provide situational updates amid the pandemic. On 12/2/20, Evan Anderson (infectious disease) provided an ​an excellent update on COVID-19​/rollout of vaccines.

Key Points:

  • mRNA vaccines​ have been remarkably effective, both ~95% and also effective against severe disease (>90%)
  • Severe reactogenicity occurs >2%. Systemic symptoms like fatigue, myalgia, and chills are more common after 2nd dose
  • Local reactions are typically more pronounced than flu vaccine but less pronounced compared to shingles vaccine (Shingrix)
  • Not wise to vaccinate entire care areas at same time
  • No need to check antibody titers after vaccination
  • Current contraindications: Pregnant women and children due to lack of data (Pfizer vaccine may be approved for those older than 12 yrs)
  • Study participants were allowed to take antipyretics
Slides used with permission.

Current pandemic situation in metro Atlanta (slide from Dan Salinas)

Top curve is total cases and bottom curve is ICU beds –both thru 11/27/20

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“Best Practice Advice” for Small Intestinal Bacterial Overgrowth– ????

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EMM Quigley, JA Murray, M Pimental. Gastroenterol 2020; 159: 1526-1532. Clinical Practice Guidelines. Full Free Text: AGA Clinical Practice Update on Small Intestinal Bacterial Overgrowth: Expert Review

This is a really lousy clinical practice guideline but a pretty good review of small intestinal bacterial overgrowth (SIBO). The reason why it is lousy: it provides virtually no recommendations on how to define/diagnose SIBO, does not recommend specific testing and equivocates on specific treatments.

Here are a few of the “best practice advice” as examples:

  • #1 The definition of SIBO as a clinical entity lacks precision and consistency; it is a term generally applied to a clinical disorder where symptoms, clinical signs, and/or laboratory abnormalities are attributed to changes in the numbers of bacteria or in the composition of the bacterial population in the small intestine
  • #5 A major impediment to our ability to accurately define SIBO is our limited understanding of normal small intestinal microbial populations
  • #6 Controversy remains concerning the role of SIBO in the pathogenesis of common functional symptoms, such as those regarded as components of irritable bowel syndrome
  • #9 There is a limited database to guide the clinician in developing antibiotic strategies for SIBO

While not providing ‘best practical advice,’ the article does provide details regarding limitations in testing, underlying pathogenesis, and potential treatment regimens for adults.

Table 3 -Provides Some Takeaway Points

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Does SMOFlipid Improve Neurocognitive Outcomes?

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M Thanhaeuser et al. J Pediatr 2020; 226: 142-148. A Randomized Trial of Parenteral Nutrition Using a Mixed Lipid Emulsion Containing Fish Oil in Infants of Extremely Low Birth Weight: Neurodevelopmental Outcome at 12 and 24 Months Corrected Age, A Secondary Outcome Analysis

This study evaluated neurodevelopmental outcomes using Bayley Scales. the authors provided a secondary outcome analysis of a double-blind randomized trial of 206 extremely low birth weight infants.  Participants received either SMOFlipid or soybean oil-based lipid. Lipids were dosed at </+ 3 g/kg/day.

Key findings:

  • Parenteral nutrition using a mixed lipid emulsion (SMOF) containing fish oil did not improve neurodevelopment of extremely low birth weight infants at 12 and 24 months corrected age
  • At 24 months of age, specifically, there was again no significant differences in any of the following areas (median values):
    • cognitive: SMOF: 95 & soybean oil: 95
    • language: SMOF: 89 & soybean oil 89
    • motor scores: SMO 94 & soybean oil: 94

Limitations: One of the reasons why this study did not find any difference is that it was not powered for assessment of neurodevelopmental outcomes. The authors provide other potential reasons:

  • DHA in SMOFlipid provided 43 mg/kg/d, while more than the soybean-lipid, is at the lower end of published fetal accretion rates (40-67 mg/kg/day)
  • DHA deficits may not have been pronounced enough in this study to see an effect of SMOFlipid on neurodevelopement
  • Full feeds were reached after 23 days (IQR, 17-37 days); thus, it is possible that infants with longer term dependency on parenteral nutrition would benefit more

My take: SMOFlipid has not been proven to have more favorable long-term neurocognitive effects than intralipid. However, for children with prolonged need for parenteral nutrition, SMOFlipid is more likely to allow full dosing which in itself may be an important contributor to better outcomes. That is, soybean-lipid emulsions are more likely to be reduced due to cholestasis and this could lead to nutritional deprivation.

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New Information on Hepatic Artery Thrombosis in Pediatric Liver Transplantation & COVID-19 Vaccine Timeline

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NE Ebel et al. J Pediatr 2020; 226: 195-201. Decreased Incidence of Hepatic Artery Thrombosis in Pediatric Liver Transplantation Using Technical Variant Grafts: Report of the Society of Pediatric Liver Transplantation Experience

This study used multicenter data from the Society of Pediatric Liver Transplantation on first-time pediatric (aged <18 years) liver transplant recipients (n = 3801) in the US and Canada (1995-2016).

Key findings:

  • 7.4% developed HAT within the first 90 days of transplantation.
  • Of those who were retransplanted, 20.7% developed recurrent HAT.
  • Those less than 1 year had the highest risk OR 1.20).
  • Lower Risk for HAT:
    • Recipients with split, reduced, or living donor grafts had decreased odds of HAT (OR, 0.59; P < .001 compared with whole grafts)
    • Adolescents aged 11-17 years (OR, 0.53; P = .03).
  • HAT increased risk of graft failure and mortality:
    • Fifty percent of children who developed HAT developed graft failure within the first 90 days of transplantation (adjusted hazard ratio, 11.87; 95% CI, 9.02-15.62)
    • Mortality risk (w/in 90 days after transplantation): adjusted hazard ratio, 6.18 (95% CI, 4.01-9.53).

The finding that split grafts had lower rates of HAT may be related to the fact that these grafts more typically come from larger donors with larger vessels. Historically, split grafts had been described as a risk factor for HAT. The authors note that high-performing centers with the lowest incidence of HAT “also tend to have high rates of living and split transplants, suggesting that surgical expertise may play a role in the decreased risk of HAT in select recipients with technical variant grafts.”

Increased rates of HAT among those who were retransplanted, in some, could be related to thrombophilic conditions; thus, consideration of anticoagulation protocol could be needed

My take: Continued efforts are needed to reduce HAT due to its impact on liver transplantation outcomes. One of the biggest risk factors is age. While this would seem to be a nonmodifiable factor, improving recognition and treatment of biliary atresia could help.

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Provocative Study: Pyloric Botox for Feeding Difficulties

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S Hirsch, S Nurko, P Mitchell, R Rosen. J Pediatr 2020; 226: 228-235. Botulinum Toxin as a Treatment for Feeding Difficulties in Young Children

This retrospective study of children, n=85, 2 months to 5 years (2007-2019) examined the effectiveness of intrapyloric botulinum toxin injection (IPBI) in children with feeding difficulties; many had vomiting (n=66) or retching (n=25). Dosing per report: 6 units/kg to a maximum of 100 units, divided in 4 injections around the pylorus. 100 units were diluted in 1 mL of normal saline to create a 10 unit/0.1 mL solution. The study excluded 27 patients who had IPBI but had insufficient data/follow-up or other disease processes.

Key findings:

  • 57 patients (67%) had partial or complete improvement in symptoms after IPBI. 10 (18%) patients were reported to have a complete response.
  • Twenty-six patients (31%) received repeat IPBI within 1 year, with only 6 patients receiving IPBI more than twice
  • “Baseline gastric emptying results did not predict IPBI response”

Limitations:

  • Retrospective study from a tertiary referral center
  • Lack of control group
  • Relatively small numbers –about 7 children per year. Given the large number of children with feeding problems followed by the Boston group, this is a highly-selected group
  • Lack of standardized evaluation to determine improvement
  • The authors state that time alone is not likely the reason for observed improvements because “our general practice at our institution is to pursue IPBI when other medical interventions have failed, and indeed these patients had been followed by our group for an average of slightly more than 1 year before receiving IPBI”

My take: Overall, I am impressed with the innovative ideas from Boston Children’s for pediatric patients with feeding problems. Yet, I am skeptical with regard to the use of IPBI for feeding difficulties; though, there may be a subset of children who benefit. Many children with complex feeding problems improve without the use of IPBI. Clearly, a randomized trial would be helpful.

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