Category Archives: Pediatric Gastroenterology Intestinal Disorder

Which Crohn’s Disease Ulcerations Are Harder to Treat — Small Bowel or Colon?

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K Takenaka et al. Clin Gastroenterol Hepatol 2020; 18: 1545-1552. Small Bowel Healing Detected by Endoscopy in Patients With Crohn’s Disease After Treatment With Antibodies Against Tumor Necrosis Factor

Methods: This was a post-hoc analysis of data from a clinical trial from 116 patients with CD (46 with ileal and 70 with ileocolonic type) who received induction and then maintenance therapy with anti-TNF agents (2013-18). Median age 29 years.

Key findings (based on findings from balloon-assisted enteroscopy )

  • Before treatment, small bowel ulcerations were present in 114 patients (98%); 42 patients (60%) with ileocolonic disease had colon ulcerations.
  • During maintenance therapy, 41/114 patients (36%) had small bowel endoscopic healing; all the patients with small bowel endoscopic healing also had colonic endoscopic healing.
  • Failure to achieve small bowel endoscopic healing was significantly associated with stricturing or penetrating disease (P = .014), lack of concomitant treatment with immunomodulators (P = .015), and having received previous treatment with an anti-TNF agents (P = .018).
  • The authors found that endoscopic healing was only 35% (36% for small bowel and 79% for colonic inflammation)

My take: Small bowel inflammation did not respond to treatment as well as colonic inflammation.  The implication of this study is that even in patients who are doing well clinically with treatment, disease progression especially in the small bowel may be ongoing.

Briefly noted: M Kayal et al. Inflamm Bowel Dis 2020; 26: 1079-1086.  Inflammatory Pouch Conditions Are Common After Ileal Pouch Anal Anastomosis in Ulcerative Colitis Patients.

  • In this retrospective study of adults with ulcerative colitis who had undergone total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA). Acute pouchitis occurred in 205 patients (53%), 60 of whom (30%) progressed to chronic pouchitis.
  • Cuffitis and Crohn’s disease-like condition (CDLC) of the pouch occurred in 119 (30%) patients and 46 (12%) patients
  • Pouch failure was noted in 6.7%
  • Only one-third of patients with chronic pouchitiis, cuffitis and CDLC responded to biologic therapy

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Does Clostridium difficile Increase the Risk of Surgical Resection in Pediatric Crohn’s Disease?

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A recent retrospective & prospective study (J Hellmann et al. Inflamm Bowel Dis 2020; 26: 1212-21. Microbial Shifts and Shorter Time to Bowel Resection Surgery Associated with C. difficile in Pediatric Crohn’s Disease. Associated editorial 1222-3) suggests that C difficile infection (CDI) is associated with an increased risk of bowel resection surgery.

In the retrospective arm with 75 pediatric patients (<22 years): Key findings:

  • 14 of 75 had positive C difficile testing (mainly PCR, especially after 2009).
  • The rate of bowel resection surgery increased from 21% in those without C. difficile to 67% in those with (P = 0.003).
  • From a Kaplan-Meier survival model, the hazard ratio for time to first surgery was 4.4 (95% CI, 1.2–16.2; P = 0.00) in patients with positive C. difficile testing in the first year after diagnosis.

Importantly, the study was unable to distinguish between C difficile colonization versus infection.

In the prospective arm with 70 patients, patients underwent meatgenomic sequencing. Those with a positive PCR assay (irregardless of symptoms or calprotectin) were considered to have CDI.

  • 10 of 70 (14%) tested positive for CDI
  • 40% of those with CD and positive CDI had a history of surgery vs 15% with negative C difficile testing
  • Fecal calprotectin levels were elevated (>250) in 40% of both those testing positive for CDI and those testing negative
  • The overall fecal microbiome composition was not statistically significantly different between CDI-positive and CDI-negative
  • There were significant differences in the fecal microbiome composition between those with prior surgery and those without prior surgery.  Depletion of Alistipes and Ruminococcus species and reduction in methionine biosynthesis were noted in patients with both C. difficile carriage and past surgery

My takes:

  1. Based on my reading, the authors assert an association of shorter time to surgery associated with CDI in the retrospective cohort.  Because testing for CDI is common in those with flare-ups, it is unclear if this is a temporal phenomenon or is a causal relationship.
  2. It is interesting that their prospective cohort did not have an increased calprotectin level in those with CDI-positivity or overall composition change in microbiome in the CDI-positive group.  It would be of interest if these studies were confined to those with cytotoxin-assay positivity which has been shown to correlate with clinical outcomes.  In previous studies, individuals with PCR-positive CDI & cytotoxin-assay negative had similar outcomes to those with negative PCR assays.

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COVID-19 -New Infection Fatality Data & How to Fix the Testing Mess

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From Annals of Internal Medicine 2020 https://doi.org/10.7326/M20-5352: J Blackburn et al. Full Text: Infection Fatality Ratios for COVID-19 Among Noninstitutionalized Persons 12 and Older: Results of a Random-Sample Prevalence Study

Background: Mortality rates have been calculated from confirmed cases, which overestimates the infection fatality ratio (IFR). To calculate a true IFR, population prevalence data are needed from large geographic areas where reliable death data also exist.

Results: The Table below suggests IFR of 0.01% for those <40, 0.12% for those 40-59, and 1.71% for those ≥60 in noninstitutionalized persons.  The Table indicates nearly a 3-fold increase risk in Non-White persons. Whites had an IFR of 0.18%; non-Whites had an IFR of 0.59%. Also, I think the Table incorrectly suggests that Females have a higher IFR than Males (but the numbers suggest that they are equivalent).

From The New Yorker, Atul Gawande: We Can Solve the Coronavirus-Test Mess Now—If We Want To

This is a lengthy article which describes some of the mistakes that we’ve made with testing, some of the technical details with various tests, pooled testing, at-home testing, wastewater testing, and how to fix testing (including assurance testing) to gain control of this pandemic.

An excerpt:

We could have the testing capacity we need within weeks. The reason we don’t is not simply that our national leadership is unfit but also that our health-care system is dysfunctional….

In the United States, getting a test is anything but easy…[And] through early August, results routinely took four days or more, making the tests essentially useless. 

“Assurance testing” has been required by countries such as Iceland, France, and Germany for travellers from abroad in order to avoid a mandatory two-week quarantine

Intestinal Barrier Function and Risk of Crohn’s Disease

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Several recent studies have examined biomarkers to predict Crohn’s disease.  A recent prospective study (W Turpin et al. Gastroenterol 2020; DOI: https://doi.org/10.1053/j.gastro.2020.08.005. Increased Intestinal Permeability is Associated with Later Development of Crohn’s Disease) sought to determine whether increased intestinal permeability, as measured by urinary fractional excretion of lactulose to mannitol ratio (LMR), is associated with future development of CD.

Methods: 1420 asymptomatic first-degree relatives (6–35 years old) of patients with CD (collected from 2008 through 2015) had LMR measured and were then followed for a diagnosis of CD from 2008 to 2017, with a median follow up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017

Key findings:

  • An abnormal LMR (> 0.03) was associated with diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64–5.63; P=3.97×10 -4).
  • This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62, 95% CI, 1.051–2.50; P=.029).

My take:  It remains unclear whether abnormal barrier function primarily precedes or follows CD development.  The authors state that these findings support a model in which altered intestinal barrier function contributes to pathogenesis.

More Data on Magnetic Sphincter Augmentation for Gastroesophageal Reflux

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In adults with gastroesophageal reflux, there is more data that magnetic sphincter augmentation (MSA) is a good option for many.  R Bell et al. Clin Gastroenterol Hepatol 2020; 18: 1736-1743. Full Text: Magnetic Sphincter Augmentation Superior to Proton Pump Inhibitors for Regurgitation in a 1-Year Randomized Trial)

Methods: Patients with moderate to severe regurgitation (assessed by the foregut symptom questionnaire) despite once-daily PPI therapy (n = 152) were randomly assigned to groups given twice-daily PPIs (n = 102) or laparoscopic MSA (n = 50) at 20 sites.

Key findings:

  • MSA resulted in control of regurgitation in 72/75 patients (96%); regurgitation control was independent of preoperative response to PPIs. It is noted that none of the patients in this study had grade C or grade D esophagitis.
  • Only 8/43 patients receiving PPIs (19%) reported control of regurgitation.
  • In the MSA group, MSA, 61 (81%) had improvements in GERD health-related quality of life improvement scores (greater than 50%) and 68 patients (91%) discontinued daily PPI use. The Demeester scores improved from 33.4 to 3.5 at 6 months post implanation
  • Esophageal acid exposure time decreased from 10.7% to 1.3% (P < .001) from study entry to 1-year after MSA.
  • Safety: No serious perioperative adverse events occurred in any arm of the study. Although 19 (39.6%) MSA patients and 10 (33.3%) MSA crossover patients reported instances of dysphagia, MSA patients reported less dysphagia at 6 and 12 months than at baseline

Discussion points from authors:

  • Relatively limited duration of follow-up, though “other studies of MSA have documented little decrease in efficacy between 1 and 5 years of follow-up”
  • The American College of Gastroenterology guidelines indicate “that surgical therapy is not recommended for patients who do not respond to PPI therapy. However, the basis for these recommendations and the types of symptoms evaluated for response to PPI therapy is unclear. Three prospective cohort studies have compared the effectiveness of laparoscopic fundoplication between PPI responsive and  nonresponsive populations and found significant symptom improvement with laparoscopic fundoplication in PPI nonresponders, though not quite as much as in PPI responders”
  • Increased bloating which is common after laparoscopic fundoplication was not evident with MSA which found a decrease from baseline.  “. Continued ability to belch was reported in 99% (n = 74 of 75) of all patients who received MSA at 12 months.”

In the associated editorial, JE Richter (Clin Gastroenterol Hepatol 2020; 18: 1685-1687 Full text: Laparoscopic Magnetic Sphincter Augmentation: Potential Applications and Safety Are Becoming More Clear—But the Story Is Not Over) notes that “erosion and migration of the MSA device have been a rare event thus far. In a total of nearly 10,000 device placements, there were 29 reported cases of erosions…Smaller devices were associated with higher rates of erosions. The 12-bead device was responsible for 18 of 29 erosions (62%) and is no longer available for implantation…To an admitted skeptic about new antireflux treatments, the available data about the symptomatic and
physiological effectiveness, durability, and safety of MSA are very impressive. I believe this procedure now deserves to be routinely done as an alternative surgical procedure to traditional fundoplication for patients with mild-moderate GERD….patients with severe GERD and structural sphincter dysfunction still need the traditional fundoplication”

My take: This study and others shows that MSA (aka Linx) is an effective treatment option for many adult patients with medically-refractory regurgitative reflux.

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It is surprising to me that almost half of the U.S. thnk that we have handled the pandemic well

Are Your Geneticists Looking For Celiac Disease in Children With Down Syndrome?

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Briefly noted: E Liu et al. JPGN 2020; 71: 252-6. Routine Screening for Celiac Disease in Children With Down Syndrome Improves Case Finding

  • Retrospective chart single center review of children with Down syndrome (2011 to 2017).
  • Prevalence of celiac disease in our population of children with Down syndrome ages 3 years or older was 9.8%.
  • 90 with celiac disease diagnosis:
    • 58 biopsy-confirmed
    • 17 with diagnosis via serology threshold in accordance with ESPGHAN
    • 9 diagnosis at outside center
    • 6 with serology but not meeting definitive criteria
  • 82% were identified through screening rather than clinical symptoms

My take: To identify celiac disease in children with Down syndrome, routine screening is needed.

Pictures from Sullivan’s Island, SC -This first picture looks out on Charleston Harbor and Ft Sumter is in the distance

IBD Update -September 2020

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Briefly noted:

Safety of Thiopurine Use in Paediatric Gastrointestinal Disease. E Miele et al. JPGN 2020; 71: 156-62. Useful review of thiopurines for IBD and for autoimmune hepatitis

The Effect of Adalimumab Treatment on Linear Growth in Children With Crohn Disease: A Post-hoc Analysis of the PAILOT Randomized Control Trial. M Matar et al. JPGN 2020; 71: 237-42. This study showed that 66 (of 78) who completed 72 weeks of treatment had improved (but not normalized) linear growth (height z-score at baseline improved from -0.62 to -0.33 (P=0.005) and normalization of weight and BMI. The presence of perianal disease was associated with diminished growth velocity.  Overall, this study adds to the literature that anti-TNF agents can reverse growth failure associated with Crohn’s disease.

Full text: Deep Remission at 1 Year Prevents Progression of Early Crohn’s Disease  RC Ungaro et al. Gastroenterol 2020; DOI: https://doi.org/10.1053/j.gastro.2020.03.039 Key finding: When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07–0.31) was significantly associated with a lower risk of major adverse outcome.  This study is reinforced by recent data published at DDW 2020 -Abstract 401: N Plevris et al. “Early Mucosal Healing Key to Long-Term Success.”  This was highlighted by Miguel Regueiro in Gastroendonews.com.  Among 375 patients, those who achieved a fecal calprotectin (FC) <250 mcg/g within one year of diagnosis, the disease progression was 65% slower than those with FC values that did not normalize within a year.  Initiation of a biologic within 3 months of diagnosis, more than quadrupled the likelihood of FC normalization within one year.

 

Weak Support For Probiotics in Acute Gastroenteritis

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Two recent well-controlled studies (D Schnadower et al.N Engl J Med 2018; 379:2002-2014, SB Freedman et al. N Engl J Med 2018; 379:2015-2026) showed that probiotic-treated children with acute gastroenteritis (AGE) did not have better outcomes than placebo-treated children. In addition, a recent AGA practice guideline recommended against the use of probiotics for most GI conditions, including in AGE.

However, a new report (H Szajewska et al. JPGN 2020; 71; 261-69) from an ESPGHAN  working group recommends that probiotics should have a role for AGE.  Several points about this report:

  1. Their recommendations are very qualified: “weak recommendation” with “low to very low certainty of evidence” for the following in descending order: S boulardiii, L rhamnosis GG, L reuteri DSM 17938, and L rhamnosus 19070 & L reuteri DSM 12246
  2. It is noted that this report has a disclaimer from ESPGHAN: “it does not represent ESPGHAN policy and is not endorsed by ESPGHAN”
  3. The authors have extensive disclosures
  4. The report notes that “despite large number of identified trials, we could not identify 2 randomized controlled trials of high quality for any strain that provided benefit when used for treating acute gastroenteritis”

Of note, the associated editorial (pg 146-47) also favors probiotics in the setting of AGE.  “These recommendations…have clarified that there is a role for probiotics in treating” AGE.

Related article (just published): F Mourney et al. The Pediatric Infectious Disease Journal: August 7, 2020 – Volume Online First – Issue –doi: 10.1097/INF.0000000000002849 A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Saccharomyces boulardii in Infants and Children With Acute Diarrhea (n=100) Key findings: The time of recovery from diarrhea was significantly shorter in the probiotic group compared with the placebo group (65.8 ± 12 hours vs. 95.3 ± 17.6 hours, P = 0.0001).

My take: Overall, probiotic effectiveness is overstated; though, some strains may be helpful for AGE.  Still, there are concerns about variation in production and quality standards even in these strains.

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Briefly Noted: How to Approach Crohn’s Disease Complicated by an Intra-abdominal Abscess

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A recent review (T Qazi, M Regueiro. Practical Gastroenterology 2020: June Issue, 10-18. Full PDF Link: Crohn’s Disease Complicated by an Intra-abdominal Abscess: Poke, Prod, or Cut?)

The article is a good review & the algorithm below provides some good guidance -if difficult to visualize, then it may be worthwhile to look at source article.

The authors propose initial management with antibiotics, minimization of steroids, nutritional support and drainage.

Medical treatment is favored after initial management:

  • Newly diagnosed Crohn’s disease
  • Extensive disease
  • No fibrostenoting disease
  • Active perianal disease

Surgical treatment is favored after initial management:

  • Long-standing disease
  • Stricture with dilatation
  • Abscess >6 cm in size
  • Prior surgical intervention

The authors note that “recent studies have suggested that roughly 30% of patients
treated with PD are able to avoid future surgical resection.”

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Trichobezoar: Don’t Do What They Did

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A recent review and case report (AF Nita et al JPGN 2020; 71: 163-70) describe an anguishing outcome after an endoscopy.  This publication is a useful, cautionary tale. In my view, the associated editorial (“MacGyver and Rapunzel in the Pediatric Endoscopy Suite” by JR Lightdale, pg 147-8) tiptoes on the issue of safety concerns of the endoscopic approach described in the review.

Case report: The authors describe a 9 year old with trichobezoar/Rapunzel syndrome who underwent a 3 hour endoscopic procedure with APC to remove the trichobezoar which was found to be composed of both human hair and doll’s hair (the latter may have contributed to complications).  In addition, the child had undiagnosed celiac disease.  Subsequent to the procedure, the child required a laparotomy; she had 18 small intestinal perforations and a gastric perforation.  The child went on to need an extensive small bowel resection (107 cm) and a 3 month hospitalization.

The authors state that a previous review had indicated only a 5% success rate for trichobezoar endoscopic removal (RR Gorter et al. Pediatr Surg Int 2010; 26: 457-63). However, they claim increased success more recently by identifying 16 of 52 (30.7%) removal rate from recent case reports.  Interestingly, one of the successful endoscopic removals cited by the authors had a respiratory arrest during the procedure (Esmali et al).

Bad advice from this article:

  • #1 The authors repeatedly suggest now that there is a >30% endoscopic success rate for endoscopic removal and thus they suggest that “it remains reasonable to attempt endoscopic retrieval” as long as a gastric trichobezoar occupies less than two-thirds of the stomach and has limited to no extension into the small bowel.
  • #2 The authors believe that “the skill mix of the endoscopist” is an important issue.

My take on their ‘learning points’:

  1. This 30% success rate should not be taken seriously due to publication bias (many unsuccessful cases are not reported) and due to treatment bias.  Many clinicians would never attempt to remove a very large trichobezoar.  Thus, the 30% success rate likely includes bezoars that may be more amenable to removal and by centers with more advanced endoscopists.
  2. The second claim about endoscopist skill is also bad advice.  First of all, some of the authors of this study have extensive endoscopic experience and yet this did not preclude a bad outcome for this child.  Secondly, in my experience, ~85% of individuals (including GI doctors) consider themselves above average; thus, it may be difficult to know if the ‘skill mix’ of the endoscopist is suitable.  Large trichobezoars are rare and no individuals will have enough experience to be considered experts.
  3. My advice: Don’t try to be MacGyver in the endoscopy suite.  Most trichobezoar cases are more suitable for surgical removal.  The most important skill of a good endoscopist is good judgement and the ability to identify cases in which an endoscopy is ill-advised.

Isle of Palms, SC