Category Archives: Pediatric Gastroenterology Intestinal Disorder

“Positioning Biologic Therapies in the Management of Pediatric Inflammatory Bowel Disease” & 14% of U.S. Infected with COVID-19

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J Breton et al. Gastroenterology & Hepatology 2020; 16: 400-14. Full text: Positioning Biologic Therapies in the Management of Pediatric Inflammatory Bowel Disease

This is a terrific summary of biologic therapies for pediatric inflammatory bowel disease. Compared to adults, the pediatric data is much more limited.  This may affect recommendations.  For example, recent AGA guidelines for moderate to severe ulcerative colitis in adults suggests that either ustekinumab or tofacitinib is generally preferable as a 2nd line agent rather than vedolizumab in patients with primary infliximab failure (Blog post: AGA Guidelines: Moderate to Severe Ulcerative Colitis).  In the chart below, vedolizumab is recognized as a preferred 2nd line agent.

In the section on vedolizumab:

The favorable risk-benefit profile makes vedolizumab an ideal therapeutic choice for pediatric IBD. However, an important limitation is its delayed onset of action, for which corticosteroid use as bridge therapy is often necessary in this population that is already at increased risk of growth failure and bone loss. Recently, Hamel and colleagues published their small, single-center experience of using concomitant tacrolimus between anti-TNFα withdrawal to vedolizumab maintenance as a corticosteroid-sparing bridge therapy in moderate to severe IBD (Ref: Hamel B, Wu M, Hamel EO, Bass DM, Park KT. Outcome of tacrolimus and vedolizumab after corticosteroid and anti-TNF failure in paediatric severe colitis. BMJ Open Gastroenterol. 2018;5(1):e000195).

This article addresses therapeutic drug monitoring:

TDM is a key component of managing IBD patients on anti-TNFα therapy. While  reactive TDM of antiTNFα agents has been adopted by societal guidelines, there is an increasing body of literature to support the benefit of proactive TDM, particularly in pediatric populations

Conclusions from authors: Anti-TNFα agents have revolutionized the management of IBD, positively modifying the natural disease history in children. Importantly, inception cohort studies of pediatric CD and UC (RISK and PROTECT, respectively) have highlighted the variable course of disease and necessity of adopting an individualized approach with early use of biologic therapy in patients at risk of severe disease progression. 

Biologics Used in Pediatric Inflammatory Bowel Disease

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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

Hemospray Efficacy and Rebleeding

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A Ofusu et al. J Clin Gastroenterol 2020. doi:10.1097/MCG.0000000000001379. The Efficacy and Safety of Hemospray for the Management of Gastrointestinal Bleeding

This systematic review and meta-analysis included 19 studies and 814 patients.

  • 212 patients were treated with Hemospray as monotherapy
  • 602 patients were treated with Hemospray with conventional hemostatic techniques.

Key findings:

  • Overall pooled clinical success after the application of Hemospray was 92%
  • Overall pooled early rebleeding rates (<7 days) after application of Hemospray was 20%
  • Overall pooled delayed rebleeding rates after the application of Hemospray was 23% (<30 days)
  • There was no statistical difference in clinical success (RR, 1.02; 95% CI, 0.96-1.08; P=0.34) and early rebleeding (RR, 0.89; 95% CI, 0.75-1.07; P=0.214) in studies that compared the use of Hemospray as monotherapy versus combination therapy with conventional therapy.

Related study: D Chahal et al. Dig Liver Dis 2020. DOI: https://doi.org/10.1016/j.dld.2020.01.009 Full text: High rate of re-bleeding after application of Hemospray for upper and lower gastrointestinal bleeds Findings (n=86): Immediate hemostasis rate was 88.4%, but there was a high rate of re-bleeding (33.7%). Most re-bleeds occurred within 7 days (86.2%)

My take: Hemospray is effective in achieving immediate hemostasis but there are high rates of rebleeding. It may be eliminated by GI tract in as few as 24 hours after use.  Thus, for lesions at high risk for bleeding, hemospray is likely more of a last resort endoscopic option.

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Eosinophilic Esophagitis -FAQs

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A recent FAQ on Eosinophilic Esophagitis By Ronak Patel, MD  Ikuo Hirano, MD, AGAF: Full Text -GIHepNews (August 2020) Eosinophilic esophagitis: Frequently asked questions (and answers) for the early-career gastroenterologist

One aspect about this review that I liked was the dietary step-up –step-down therapy figure:

Reference: J Molina-Infante et al. J Allergy and Clincal Immunology. DOI:https://doi.org/10.1016/j.jaci.2017.08.038 Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: The 2-4-6 study Results:  A TFGED (2-food) achieved EoE remission in 56 (43%) patients, with no differences between ages. Food triggers in TFGED responders were milk (52%), gluten-containing grains (16%), and both (28%). EoE induced only by milk was present in 18% and 33% of adults and children, respectively. Remission rates with FFGEDs (4-food) and SFGEDs (6-food) were 60% and 79%, with increasing food triggers, especially after an SFGED. Overall, 55 (91.6%) of 60 of the TFGED/FFGED responders had 1 or 2 food triggers. Compared with the initial SFGED, a step-up strategy reduced endoscopic procedures and diagnostic process time by 20%.

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IB-Stim (Neuro-Stim) for Adolescents with Irritable Bowel

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A recent study (A Krasaelap et al. Clin Gastroenterol Hepatol 2020; 18: 1987-1994.  Efficacy of Auricular Neurostimulation in Adolescents With Irritable Bowel Syndrome in a Randomized, Double-Blind Trial) with data from a double-blind trial provides evidence of short-term (4 week) efficacy of auricular neurostimulation therapy (aka. IB-Stim or Neuro-Stim).

Key findings:

  • The IB-Stim group (n=27, median age 15 years) had a ≥30% reduction in abdominal pain in 59% compared to 26% of the sham group (n=23)
  • A symptom response scale score of 2 or more was observed in 82% of patients who received IB-Stim vs 26% of patients in the sham group ( P ≤ .001)

Discussion points:

  • The authors indicate that the NNT for IB-Stim is 3 compared to 6-14 for other medical therapies (lubiprostone, linaclotide, and rifaximin)
  • The effects of IB-Stim were NOT sustained at follow-up 8-12 weeks and there was no significant improvment in functional disability or anxiety.  “The lack of long-term effect…likely reflects insufficient statistical power.”  The authors indicate that longer or repeated courses could be needed

My take: This study indicates that IB-Stim can be helpful, at least in the short term, for adolescents with IBS.  More studies showing long-term benefit would be helpful.

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Why Celiac Serology Needs To Be Looked At Differently in Children with Type 1 Diabetes

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A recent study (M Wessels et al. J Pediatr 2020; 223: 87-92. Raising the Cut-Off Level of Anti-Tissue Transglutaminase Antibodies to Detect Celiac Disease Reduces the Number of Small Bowel Biopsies in Children with Type 1 Diabetes: A Retrospective Study) recommends changing the approach to celiac disease (CD) diagnosis in children with Type 1 Diabetes Mellitus (T1DM).

Background: The prevalence of CD among patients with T1DM is between 3-10%

Using a retrospective observational cohort with 63 children, the authors recommend raising the cut-off from performing biopsies from 3 times the ULN to 11 times ULN.

Here’s why:

  • This change in increases the specificity from 36% to 73% while reducing sensitivity from 96% to 87%.  In addition, this improves the positive predictive value from 88% to 94%, but lowered negative predictive value from 67% to 53%.  Overall, this leads to a reduction in “unnecessary biopsies.”
  • The authors note that while the serology sensitivity is reduced, it is still acceptable and justified because “normalization of elevated TG2A  can occur in up to one-third of patients.”
  • Another finding from this cohort was that 55% of children with Marsh 0 or 1 histology were symptomatic, indicating that symptoms are not specific for CD.

While the authors have recommended a higher threshold and advocated for repeating serology ~3 months later in those with lower titers, the associated editorial by Stefano Guandalini makes the following points:

  1. Raising the titer threshold would leave 13% of patients with celiac disease undiagnosed (or at least with a delay in diagnosis)
  2. “For lower titers, the physician will have to apply his or her knowledge and conscience in each individual case…we must be mindful of the serious risk of missing too many patients with celiac disease by applying a high threshold, a risk probably outweighing that of an unnecessary biopsy.”

My take: This study shows that in children with T1DM who have abnormal lower-value celiac serology, a careful discussion with parents is needed about the merits of endoscopy or deferring until persistent positivity.

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Taken near Hunley bridge, Isle of Palms, SC

IBD Update -September 2020

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EM Kim et al. Inflamm Bowel Dis 2020; 26: 1232-38. Mucosal Eosinophilia Is an Independent Predictor of Vedolizumab Efficacy in Inflammatory Bowel Diseases n=65 patients. In IBD cohort, colonic eosinophilia (340 +/- 156 vs 236 +/- 124) was associated with clinical non-response to vedolizumab (as was prior anti-TNF treatment). In those with ulcerative colitis, mean eosinophil count was 438 in nonresponders compared to 299 in responders. In those with Crohn’s disease, colonic biopsies showed a non-significant increase in eosinophil count in non-responders compared to responders: 352 vs. 232.

MA Sofia et al. Inflamm Bowel Dis 2020; 26: 1251-9. Poor Sleep Quality in Crohn’s Disease Is Associated With Disease Activity and Risk for Hospitalization or Surgery

  • Ninety-two CD and 82 control subjects
  • Crohn’s disease subjects with Pittsburgh Sleep Quality Index (PSQI) >5 more often had inflammatory phenotypes and reported increased benzodiazepine and psychiatric medication use. Crohn’s disease subjects with PSQI >5 also reported more night awakenings due to pain and bathroom use.
  • The PSQI correlated with HBI
  • PSQI >8 was predictive of surgery or hospitalization (hazards ratio 5.37; 95% confidence interval, 1.39-27.54).

My take: This study indicates that poor sleep is a marker for increased adverse outcomes/disease activity.  It may be that sleep disturbance is due to increased disease activity or this may be a bidirectional issue in which poor sleep triggers more disease activity as well.

A Ricciuto et al. Clin Gastroenterol Hepatol 2020; 18: 1509-1517. Primary Sclerosing Cholangitis in Children With Inflammatory Bowel Diseases Is Associated With Milder Clinical Activity But More Frequent Subclinical Inflammation and Growth Impairment

This retrospective study provides additional information on the observation that children with PSC often have subclinical disease; it is similar to a prospective study by the same group in 2018 (n=37):  (prior blog post: Active Colitis More Likely in Children in Clinical Remission Who Have IBD and PSC) Key finding: Higher proportions of children with PSC-IBD had backwash ileitis, pancolitis, and rectal sparing, and more severe right-sided disease, than controls (P < .05). Conclusions: “Despite the mild clinical activity of IBD in patients with PSC, lack of symptoms does not always indicate lack of mucosal inflammation. Children with PSC-IBD have greater growth impairments compared with children with ulcerative colitis or IBD-unclassified.”

“Implementing psychological therapies for gastrointestinal disorders in pediatrics”

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Bonney Reed, Jessica Buzenski & Miranda A.L van Tilburg.  Expert Review of Gastroenterology & Hepatology (2020), DOI: 10.1080/17474124.2020.1806055 Full Text: Implementing psychological therapies for gastrointestinal disorders in pediatrics

This article is a useful and up-to-date review on the role of psychology to treat children with gastrointestinal disorders, particularly targeting functional GI disorders as well as children with inflammatory bowel disease. Also, I want to recognize Bonney and Jessica who have been so helpful for so many of our patients.

Areas covered:

  • Cognitive behavioral therapy (CBT)
  • Gut-directed hypnotherapy
  • Biofeedback-assisted relaxation training
  • E-treatment/telemedicine
  • Emerging therapies: Mindfulness, and Acceptance and Commitment therapy

Resources/Referrals:

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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.

Proactive Therapeutic Drug Monitoring in Pediatric Crohn’s disease -Better Outcomes

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Y Gofin et al. Inflamm Bowel Dis 2020; 26: 1276-82.  Therapeutic Drug Monitoring Increases Drug Retention of Anti–Tumor Necrosis Factor Alpha Agents in Pediatric Patients With Crohn’s Disease

Retrospective study with 197 pediatric participants (2007-2018)

Key findings:

  • Compared with the TDM- group (n=98), the TDM+ group (n=99)
    • longer drug retention time (mean ± SE, 45.0 ± 2.7 vs 33.5 ± 2.4 months; P = 0.001)
    • lower hospitalization rate per patient per year (mean ± SE, 0.51 ± 0.7 vs 0.92 ± 0.81; P < 0.001)
    • higher treatment intensification rate (70% vs 18%; P < 0.001).
  • Analysis of the entire cohort showed a longer retention time for adalimumab vs infliximab (45.3 ± 2.8 vs 34.8 ± 2.5 months; P = 0.007)

My take: This is another study showing utility of proactive therapeutic drug monitoring

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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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