Category Archives: Pediatric Gastroenterology Intestinal Disorder

Is GLP2 Worth $300K per Year?

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E Ramos Boluda et al. JPGN 2020; 71: 734-739. Experience With Teduglutide in Pediatric Short Bowel Syndrome: First Real-life Data

S Hill. JPGN 2020; 71: 697-698 (editorial) Use of GLP-2 May Herald a New Era of Improved Outcome of Short Bowel Syndrome-associated Intestinal Failure

The study and associated editorial highlight the effectiveness of GLP-2 in a prospective cohort of 17 patients with short bowel syndrome. It is noted that Dr. Hill has received funding from the pharmaceutical manufacturer of the product.

Key findings:

  •  A total of 12 of 17 patients achieved parenteral independence: 3 patients after 3 months of treatment, 4 patients at 6 months, and 5 after 12 months.
  • The percentage able to wean off parenteral nutrition was 17%, 44%, and 60% at 3, 6, and 12 months respectively. Only 1 patient did not exhibit improvement
  • Plasma citrulline levels, a marker for enteral autonomy, increased from a baseline average of 20 micromol/l to 37.5, 46.75, and37.9at 3, 6, and 12 months respectively.
  • Adverse reactions included abdominal pain 30%, nauseas 18%, injection-site reactions 22%, and headache 16%.

Both the editorial and the study comment briefly on the cost of the therapy. The editorial also notes the current recommendation for surveillance endoscopy in view of a hypothetical risk of malignancy.

My take: Is GLP2 Worth the Cost? It probably depends on who is paying and long-term safety data. Perhaps, we will develop tools to improve prediction of which patients will achieve enteral autonomy with GLP2 who would otherwise require ongoing parenteral nutrition.

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Outcome of Zen Magnets v. Consumer Product Safety Commission

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PT Reeves, B Rudolph, CM Nylund. JPGN 2020; 71:699-703. Magnet Ingestions in Children Presenting to Emergency Departments in the United States 2009–2019: A Problem in Flux

When the 10th Circuit Court, with judges Gorsuch, Ebel, and Bacharah, rolled back high-powered magnet regulations in 2016, it was expected that this would result in more suffering in children. The referenced article by Reeves et al documents the effects of this decision.

Background: In 2016, the Zen Magnets decision resulted in magnets returning to the market with warning labels “but not performance standards favored by NASPGHAN (ie, making magnets either too large to swallow or too weak to cause harm).” In this study, the authors used data from the National Electronic Injury Surveillance System (NEISS), a database of consumer product injuries.

Key findings:

  • When stratified by time period, suspected magnet ingestion (SMI)per year was 1598 during off-market period (when product was banned) compared with 2826 during on-market period.
  • An estimated 23,756 children (59% males, 42% < 5 years old) presented with a SMI from 2009 to 2019.
  • There was an average annual case increase of 6.1% (P = 0.01).
  •  After 2017, there was a 5-fold increase in the escalation of care for multiple magnet ingestions (estimated n = 1094; CI 505–1686). “Escalation of care” refers to cases designated as ‘treated and transferred,’ ‘treated and admitted/hospitalized,’ or ‘held for observation.’
  • More data on this topic from CPSC 124 page report: (Link) Informational Briefing Package Regarding Magnet Sets

My take: Regulatory action is needed to prevent harm in children from these high-powered magnets.There are two companion bills in Congress which are in committee, one entitled “Magnet Injury Prevention Act.” These are clearly needed given previous judicial branch ruling.

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“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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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

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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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

A Definite Maybe: Antibiotics for Acute Severe Colitis

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D Turner et al. Inflamm Bowel Dis 2020; 26: 1733-1742. Antibiotic Cocktail for Pediatric Acute Severe Colitis and the Microbiome: The PRASCO Randomized Controlled Trial

This randomized study with 28 children with acute severe ulcerative colitis (ASUC) (PUCAI > /= 65) tried to determine if antibiotics with IV corticosteroids resulted in improved outcomes compared to IV corticosteroids alone. Most in the antibiotic group received the following for 3 weeks:

  • Vancomycin 250 mg 4/day (if less than 8 years, then 125 mg 4/day)
  • Amoxicillin 50 mg/kg/day divided into 3/day dosing (max 500 mg/dose)
  • Metronidazole 5 mg/kg/dose 3/day (max 250 mg/dose)
  • Doxycycline 2 mg/kg/dose 2/day (children less than 7 years rec’d ciprofloxacin 10 mg/kg 2/day -max 250 mg/dose)

Key findings:

  • The mean day-5 PUCAI was 25 ± 16.7 in the abx/steroid combination group vs 40.4 ± 20.4 in the steroid monotherapy group (P = 0.037)
  • Median calprotectin values were lower in the abx combination group at day 5 (1202 vs. 2170, P=0.24) and at discharge (1210 vs 1840, P=0.695)
  • The need for 2nd line rescue therapy was low in both groups: 19% in abx group and 17% in the steroid group
  • Within 1 year, 3/16 (19%) in the abx combination group had had a colectomy compared with 2/12 (17%) in the steroid monotherapy.
  • The authors found no correlation between microbial features/microbiome at admissioin and clinical response 5 days later

In their discussion, the authors note that if antibiotics had a treatment benefit as high as 30% in avoiding second-line treatment (ie, 14% in intervention arm), “randomization of 1228 children would be required to show such a difference with a power of 80%.”

My take: I agree with the authors who state that “antibiotics cannot be routinely recommended until larger studies demonstrate a reduced need for second-line treatment or colectomy.”

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Ravenel Bridge, Charleston, SC

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

What about Combination Therapy with Adalimumab?

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M Matar et al. Inflamm Bowel Dis 2020; 26: 1627-1635. Free full text link: Combination Therapy of Adalimumab With an Immunomodulator Is Not More Effective Than Adalimumab Monotherapy in Children With Crohn’s Disease: A Post Hoc Analysis of the PAILOT Randomized Controlled Trial

Methods: Participants (n=78, ages 6-17 years) in this study were part of the PAILOT trial; they were naïve to biologic therapy with moderate to severe Crohn’s disease. This was a randomized controlled trial aimed to evaluate proactive vs reactive therapeutic drug monitoring in children with Crohn’s disease (CD) treated with adalimumab. 

Key findings:

  • There was no significant difference in the rates of sustained corticosteroid-free clinical remission (25/34, 73%, vs 28/44, 63%; P = 0.35) or sustained composite outcome of clinical remission, C-reactive protein ≤0.5 mg/dL, and calprotectin ≤150 µg/g (10/34, 29%, vs 14/44, 32%; P = 0.77) between the combination group and the monotherapy group, respectively.
  • Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but was numerically higher in the monotherapy group. The monotherapy group had three patients undergo ileo-cecal resection.

The discussion reviews a number of studies that have compared combination and monotherapy. One key point is that this study enrolled children who were naïve to biologic therapy; thus, combination therapy may be more useful in those who have failed a previous biologic, particularly if the loss of response was immune-mediated.

My take: This study indicates that combination therapy is likely not routinely needed in children who start adalimumab and who are naïve to biologic therapy. Another finding of interest is the relatively low sustained composite outcome of clinical remission, approximately 30; this outcome combined clinical remission with biological markers. ~30%

Pitt Street Bridge Park, Mt Pleasant SC

Surviving Pediatric Intestinal Transplantation

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AK Balla et al. JPGN 2020; 71: 617-623. Factors Associated With 5- and 10-Year Survival After Intestinal Transplantation in Infants and Children

Methods: Retrospective chart review of 86 patients transplanted between 2003 and 2013

Key findings:

  • Intestinal graft survival was 71% and 65% after 5 and 10 years, respectively
  • Five-year graft survival was attained in 79% of patients with a history of anatomic intestinal failure (n=63) compared with 45% with functional intestinal failure (n=22) (P = 0.0055).
  • In their cohort, graft-versus-host and post-transplant lymphoproliferative disease were 11 times greater and 8 times greater in the functional compared with anatomic intestinal failure group. “Severe functional gastrointestinal diseases are more likely to be component of inherited multisystem disorders not fully correctable with ITx (intestinal transplantation) alone.”
  • Graft survival depends on avoidance of severe infectious and immunological complications including GVHD, whereas inclusion of a liver graft provides no obvious survival benefit

My take: In this cohorts, intestinal transplantation outcomes have improved for anatomic intestinal failure but not for functional intestinal failure. “Reduced success with functional intestinal failure may reflect inherently increased susceptibility to complications in this group.”

IBD Update (November 2020)

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W Reinisch et al. Inflamm Bowel Dis 2020; 1562-1571.Full Text: Association of Biomarker Cutoffs and Endoscopic Outcomes in Crohn’s Disease: A Post Hoc Analysis From the CALM Study n=244.

  • The proportion of patients who achieved the primary end point CDEIS <4 and no deep ulcers was significantly greater for those with FC <250 µg/g (74%; P < 0.001)
  •  Fecal calprotectin <250 µg/g, CRP <5 mg/L, and CDAI <150 gave a sensitivity/specificity of 72%/63% and positive/negative predictive values of 86%/42% for CDEIS <4 and no deep ulcers 48 weeks after randomization

My take: Fecal calprotectin levels are useful for monitoring mucosal healing. Levels less than 250 are encouraging. Levels less than 100 are better.

Proportion of patients achieving mucosal healing (CDEIS <4) and no deep ulcers in (B) all patients by FC cutoff at week 48 after randomization

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S Danese et al. Clin Gastroenterol Hepatol 2020; 18: 2526-2534. Full text link: Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis “We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies.” n=168. Key findings:

  • Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo)
  • At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group.

X Zhuang et al. Inflamm Bowel Dis 2020; 26: 1636-1647. Full text: Fecal Microbiota Alterations Associated With Clinical and Endoscopic Response to Infliximab Therapy in Crohn’s Disease

Methods: Microbiota was prospectively analyzed in 49 patients with active CD at baseline, week 6, and week 30

Key Findings:

  • Increased proportions of Lachnospiraceae and Blautia were associated with IFX efficacy; the combined increase of these taxa at week 6 showed 83.4% and 84.2% accuracy in predicting clinical response at weeks 14 and 30, respectively, with a predictive value of 89.1% in predicting endoscopic response at week 30
  • IFX diminished CD-related gut microbial dysbiosis by modifying microbiota composition and function