Category Archives: Pediatric Gastroenterology Intestinal Disorder

Brain-Gut Axis in 2017

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“Brain–gut interactions and maintenance factors in pediatric gastroenterological disorders. Recommendations for clinical care.” B Reed-Knight et al. Clinical Practice in Pediatric Psychology, 2017; 5: 93-105.

A summary of this review article by Sharon Berry, PhD, ABPP, Past President, Society of Pediatric Psychology:

This review article describes the brain–gut axis as a means to increase understanding of how biological mechanisms implicated in a range of pediatric GI disorders interact with psychological and contextual factors to maintain GI symptoms and (b) provide practical ways for pediatricians and other healthcare providers to  incorporate a discussion of the brain–gut axis into patient education for pediatric GI disorders.

Biological mechanisms of the brain–gut axis including alterations in pain processing, the stress response system, and gut microbiome activity are reviewed. Psychosocial factors that contribute to or maintain disturbances in the brain–gut axis are discussed with implications for clinical assessment and intervention. The authors assert that a mutual understanding by patients, families, and providers alike of the relevant brain–gut interactions and the biopsychosocial model, in general, will serve as a foundation for successful delivery of and adherence to medical and psychological interventions. Important clinical conclusions include:

  • Early discussion of the brain-gut axis may reduce resistance to integrated behavioral or psychological treatment for pediatric gastroenterological disorders.
  • Sample visual aids and descriptive scripts are available within this review to guide discussions of the brain-gut axis with patients and families for a range of pediatric GI disorders.

My take: This article serves is a useful resource for pediatric psychologists to better understand the ideas of visceral hypersensitivity, stress response, and biological triggers (eg. gut microbiome, infections) for gastrointestinal disorders. Its discussion of biopsychosocial assessment and psychological interventions are helpful for pediatric gastroenterologists to understand the psychological approaches toward treatment.

Related blog posts:

NPR: Banana Diet for Celiac Disease

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A recent report from NPR highlights a previous diet for celiac disease -the banana diet. While celiac disease had been discovered in the 1890s by Dr. Samuel Gee, the role of gluten was not understood until WWII.

NPR: Doctors Once Thought Bananas Cured Celiac Disease

Here’s an excerpt:

a high-calorie, banana-based diet [was] invented by Dr. Sidney Haas in 1924. The diet forbade starches but included numerous daily bananas, along with milk, cottage cheese, meat and vegetables…

Haas arrived at his banana diet through an honest error — one that, unfortunately, had serious repercussions for people with celiac disease. In his 1924 paper, he wrote of a town in Puerto Rico where “dwellers who eat much bread suffer from [celiac] sprue while the farmers who live largely on bananas never.”

Haas skipped over the role of wheat and focused instead on the exotic bananas, which he thought held curative powers…

But Haas’ honest error led to serious consequences. As the children recovered, wheat was reintroduced.

It was a Dutch pediatrician, Willem Karel Dicke, who first realized that wheat might be linked to celiac disease. He noticed that in the last few years of World War II, when bread was unavailable in the Netherlands, the mortality rate from celiac disease dropped to zero. In 1952, Dicke and his colleagues identified gluten as the trigger for celiac disease, and the gluten-free diet was born.

 

Vaccine for Celiac Disease

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A recent study (KM Kemppainen et al. Clin Gastroenterol Hepatol 2017; 15: 694-702, editorial 703-5) showed that gastrointestinal infections can trigger celiac disease (CD) and that immunization with the rotavirus vaccine was protective against developing CD.

This study is part of the TEDDY study: The Environmental Determinants of Diabetes in the Young.  The TEDDY cohort involves more than 8000 children who are part of an international prospective cohort who carry genes (HLA-DR-DQ genotypes) with increased risk for diabetes and CD. In this particular group, the authors identified 6327 children who were 4 yrs old by March 2015.

Key Definition: CD autoimmunity (CDA) -children who tested positive for tTG IgA at their annual visit and remained persistently positive 3 months later

Key Findings:

  • Gastointestinal infections (n=13,881) but not respiratory infections (n=79,816) were associated with an increased risk of CDA.  CDA risk was increased within the 3 months of the GI infection.
  • 732 of 6327 (11.6%) developed CDA.  In this cohort, 318 underwent duodenal biopsy and 283 (90%) had biopsy indicative of CD (Marsh score >1). Thus, in their cohort, there is variability in the onset of CD from the onset of CDA.
  • Risk of CDA was reduced in children vaccinated against rotavirus and introduced to gluten before age 6 months (HR =0.57).
  • The exact risk depending on interaction with multiple factors including breastfeeding, HLA genotype, seasonality of birth, and timing of gluten introduction. Timing of infection plays a role as well, as earlier exposure to GI infections earlier in life was associated with a decreased risk of celiac disease.

This reference should be kept handy for vaccine advocates.  Not only can vaccines prevent infections, but they have now been shown to prevent an autoimmune disease (CD).  In addition, previous studies have shown that vaccines can prevent cancers, including hepatocellular carcinoma and cervical cancer.

My take (modified from editorial): This study “demonstrates the power of rigorously conducted prospective studies to reveal complex interactions among genetic and environmental factors.” In addition, this study shows that preventing rotavirus infection with vaccination lowers the risk of celiac disease.

Related blog posts:

SuperPoopers CCFA Team 2017

IBD Resources for Clinicians/IBD Tweets

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Another website with a few useful resources:

  • Steroid taper calendar -helps develop a calendar (can use to print out or take a picture)
  • Imaging risk calculator -this is not that great.  In essence if you have a patient present to ER with a CRP of 1 mg/dL and ESR of 20, it states that risk of a complication like a perforation is “NOT LOW” and to consider imaging
  • IBD School Video collection -links to UM website

Note -therapeutic drug monitoring may be more useful in children due to their changing size.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Tofacitinib Induction and Maintenance for Ulcerative Colitis

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W Sandborn et al. N Engl J Med 2017; 376:1723-1736 May 4, 2017DOI: 10.1056/NEJMoa1606910

Abstract from NEJM:

BACKGROUND

Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy.

 

METHODS

We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.

 

RESULTS

In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.

 

CONCLUSIONS

In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo.

The Truth about Probiotics: Constipation Version

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Families are often surprised to learn my opinion about probiotics.  The “truth” about probiotics is that they are poorly regulated/lack rigorous production standards and are mostly ineffective for many of the conditions for which they have been promoted.  Even in conditions in which there is some effectiveness (eg. antibiotic-associated diarrhea), the number of persons needed to treat for one person to benefit is fairly high.

In addition, when someone says that they are taking a probiotic, many families do not understand the idea of “strain” specific effects.  I tell families that if they see a “dog in yard” sign that they do not know if that is a poodle of a pit bull.  With probiotics, similarly you often do not know if you are getting a pit bull or a poodle.

As a consequence, I think negative studies like a recent report (K Wojtyniak et al. J Pediatr 2017; 184: 101-05) are helpful. In this study, the authors examined the effectiveness of Lactobacillus casei rhamnosus Lcr35 (Lcr35) in the management of constipation.

This randomized, double-blind, placebo-controlled trial was conducted in 94 children <5 years of age. Dose: 8 x10 to the 8th CFU twice daily x 4 weeks.

Key findings:

  • “Lcr35 as a sole treatment was not more effective than placebo in the management of functional constipation.” In fact, the placebo group had a greater increase in bowel movement frequency than the treatment group.
  • Both groups had improvement -more than half in each group (total 52 of 81 who completed study) had reached endpoint of 3 or more BMs/week without soiling.

My take: Probiotics often are ineffective.  This study showed that Lcr35 was NOT helpful for pediatric constipation.

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Claude Monet, La Rue Montorgueil

 

 

Celiac Disease and Mode of Delivery -Perhaps Not Very Consequential

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Briefly noted:

A recent study (E Lionetti et al. J Pediatr 2017; 184: 81-6) did NOT find an association between mode of delivery and the development of celiac disease (CD).

After a telephone interview to confirm mode of delivery, the authors identified 431 children at high risk for CD and compared the rates of celiac autoimmunity (serology-positive) and overt CD that developed by age 5 years:

  • CD autoimmunity –cesarean vs vaginal:  24% and 19% (P=.2)
  • Overt CD –cesarean vs vaginal:  19% and 14% (P=.2)

While neither reached statistical significance, there was a higher rate in those born by cesarean mode.  The lack of a statistical association could be a reflection on sample size or the specific population that was studied.  However, more likely, this suggests that “the role of intestinal microbiota at birth in the pathogenesis of immune mediated disorders has been overestimated.”

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La Source, Jean Auguste Dominque Ingres, Musee d’ Orsay

 

Caution with Celiac Genetic Testing Plus Two

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Conventional wisdom and previous studies have indicated that negative testing for HLA-DQ8 and HLD-DQ2.5 alleles makes a diagnosis of celiac disease (CD), now or in the future, very unlikely.  While ~60% of the population has one of these alleles, testing negative for these alleles has been regarded as having a high negative predictive value (>99%) and can be valuable in cases of equivocal diagnosis.

The authors of recent report (F Fernandez-Banares et al. Clin Gastroenterol Hepatol 2017; 15: 594-96) challenged this wisdom, noting that there is expected to geographical variation in the presence of these alleles. The goal of their study was to assess the prevalence of HLA-DQ2.5/8 among CD patients in Spain by reviewing previous studies; 12 studies were included. To be included, patients had to have villous atrophy, positive serology and available genotyping.

Key finding:

  • Among 2963 Spanish CD patients, 3% “might be negative for HLA-DQ2.5/8.”

This is a brief report.  It is expected that limitations would relate to the accuracy of genotyping and of excluding other causes of villous atrophy.

My take: (from the authors) “This information highlights the need to be cautious when ruling out CD only on the basis of genetics.”

Related blog posts:

Briefly noted:

L Kivela et al. J Pediatr 2017; 183: 115-21.  This study divided children with CD into those identified via screening (n=145) and those identified due to clinical symptoms (n=359). Key findings:

  • There were no differences in serology or histology between the two groups
  • More than half (51.8%) of screen-detected patients had symptoms at diagnosis, but typically these were milder than in the clinically-detected group.
  • Anemia was more common in the ‘clinical group’ 22.9% vs 7.1% (screen group) as was poor growth (36.9% vs. 15.7%).

AJ Irvine et al. Am J Gastroenterol 2017; 112: 65-76. (Thanks to Ben Gold for this reference) In this systemic review with 15,256 individuals (& 9,275 with irritable bowel), “prevalence of positive celiac serology and biopsy-proven CD was significantly higher in subjects with symptoms suggestive of IBS vs. healthy controls.”  The odds ratio for serology-positive and/or biopsy-proven CD ranged from 2.75 to 4.48, though there was no significant increase in these ORs for North American studies.

Palace of Versailles

 

Celiac Disease and Psychological Problems

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A recent study (A Butwicka et al. J Pediatr 2017; 184: 87-93) describes an increased rate of childhood psychiatric disorders among children with celiac disease (CD).

The authors used a nationwide registry (in Sweden) with 10,903 children with celiac disease, 12,710 siblings, and more than 1 million control patients. The median age at diagnosis was 3 years and median duration of followup was 9.6 years.

Key findings:

  • CD patients had a 1.4 fold greater risk of psychiatric disorders, including mood disorders, eating disorders, behavioral disorders, and ADHD.
  • CD siblings did not have an increased risk.
  • 7.7% of children with CD were diagnosed with a psychiatric disorder

Limitation: The actual reported incidence of psychiatric disorders seems low in both the CD patients and controls.  It is possible that some of the difference could be related to selection bias. Patients with (undiagnosed) psychiatric disorders may be more likely to be anxious, and seek out medical attention for their GI complaints;  this could precede a diagnosis of CD.

Strengths: This study has large numbers of patients and the data was prospectively obtained.

The association with increased psychiatric problems could have a biologic basis or be related to the toll of chronic gastrointestinal symptoms prior to diagnosis and the difficulty of managing CD.

My take: This is an intriguing study and suggests that patients with CD are more likely to be diagnosed with a psychological disorder.  Whether CD itself or the preceding symptoms trigger this diagnosis is uncertain.

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Paris from Notre Dame

Is Propofol Safe in Pediatric Patients with Food Allergy and Eosinophilic Esophagitis?

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According to a recent study (P Mehta et al. JPGN 2017; 64: 546-49), propofol was safe in pediatric patients with eosinophilic esophagitis (EoE) and food allergy.

This finding was based on a retrospective study of 1365 upper endoscopies (2013-2014).  Though, propofol was used less frequently, “there was no difference in complication rates relative to propofol use.”

Specifically, egg or soy allergy patients had 38 procedures; 114 children had EoE (without known egg or soy allergy) and 27 and EoE and egg or soy allergy.

This study is important because propofol is used frequently in patients with egg and soy allergies despite a contraindication warning on the package insert. Nevertheless, this study does not provide a definitive answer due to the very low rates of allergic reactions to propofol (~1:10,000 to 1:20,000).  In addition, the diagnosis of food allergy in this study relied on review of the medical record.

My take: This study is limited in scope but did not identify any significant safety concerns with propofol in patients who had EoE and/or egg/soy allergies.

Palace of Versailles