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Pediatric Gastroenterology

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Category Archives: Pediatric Gastroenterology Intestinal Disorder

Expert Guidance on Pediatric Postoperative Crohn’s Disease

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A recent NASPGHAN clinical report (JB Splawski et al JPGN 2017; 65: 475-86) updates recommendations to lower the rate of postoperative recurrence in pediatric Crohn Disease (CD).  In this report, after review of a number of studies, the authors provide a management algorithm (Figure 1).  In addition, they review risk factors for surgery/postoperative recurrence in CD.

Key points:

  • “Endoscopic recurrence precedes clinical recurrence, and is a better predictor of the risk for future surgery.”
  • “Anti-TNF agents appear to be the most effective treatment in preventing postoperative recurrence.”  These agents “can be started as early as 4 weeks after surgery.”
  • “Prophylactic treatment to prevent recurrence rather than treating after the disease recurs, appears to be more effective in preventing further surgery.”
  • “Early postoperative surveillance for disease recurrence allows for a change in management to prevent complications that may lead to further surgery.” The authors note that fecal calprotectin (and lactoferrin) return to baseline around 2 months after surgery, and “monitoring disease activity postsurgery with these tests may help determine appropriate selection for more invasive testing such as endoscopy.”

My take: The authors emphasize that “whatever treatment is chosen, early surveillance for disease recurrence is clearly needed.”  In addition, anti-TNF agents are most likely to lower risk of further surgery.

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Silver Bridge, Colorado River, Bright Angel Trail. Grand Canyon

 

Does It Matter How Hard Your Poop Is?

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A recent study (MH Vriesman et al. J Pediatr 2017; 190: 69-73) with 1835 children examined the issue of stool consistency, comparing the Bristol Stool Scale (BSS) and the Questionnaire on Pediatric Gastrontestinal Symptoms-Rome III (QPGS-RIII). Most of the patients in this study were older children, with 803 (43.7%) age 8-12 years and 1032 (56.3%) ≥13 years.

Key findings:

  • Surprisingly (to me) there only slight agreement between BSS and QPGS-RIII for assessing stool consistency (κ = .046; P=.022).
  • With the BSS, hard stools (types 1 & 2) were reported more frequently than QPGS-RIII: 18.0% vs. 7.1%.
  • Both scales reported similar levels of functional constipation, 9.3% for BSS and 8.6% for QPGS-RIII. The presence of hard stools or painful defecation is only 1 of 6 Rome criteria for the diagnosis of functional constipation.

These results indicate significant variability in how often pediatric patients considered their stools hard based on the instrument (BSS vs QPGS-RIII).  The reason why there is fairly close agreement on functional constipation is due to the fact that Rome III criteria combine the presence of hard stools and painful defecation into a single criteria and the fact that there are multiple criteria needed.  “Not all children with hard stools have painful defecation and vice versa, with only 21% of children with painful defecation reporting hard stools.”

My take: This study suggests that painful defecation is more important to ascertain than if the stools are hard. In addition, this may explain why softening the stools as a stand alone strategy is not effective in many children.

Related study: S Muddasani et al. J Pediatr 2017; 190: 74-8.  This retrospective study showed that pelvic floor physical therapy was effective in the majority of children (n=64,mean age 8.7 yrs) with fecal incontinence due to pelvic floor dyssynergia. It is notable that there were only two physical therapists involved; thus, in order to replicate these results, one would need quite capable PTs.

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Does Celiac Disease Increase the Likelihood of Clostridium difficile infections?

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Thanks to Mike Hart for the following reference:  Risk of Clostridium difficile in patients with Celiac Disease: A Population-Based Study B Lebwohl et al. AJG 2017; doi:10.1038/ajg.2017.400

Abstract

Objectives:

Patients with celiac disease are at increased risk for infections such as tuberculosis, influenza, and pneumococcal pneumonia. However, little is known about the incidence of Clostridium difficile infection (CDI) in patients with celiac disease.

Methods:

We identified patients with celiac disease based on intestinal biopsies submitted to all pathology departments in Sweden over a 39-year period (from July 1969 through February 2008). We compared risk of CDI (based on stratified Cox proportional hazards models) among patients with celiac disease vs. without celiac disease (controls) matched by age, sex, and calendar period.

Results:

We identified 28,339 patients with celiac disease and 141,588 controls; neither group had a history of CDI. The incidence of CDI was 56/100,000 person-years among patients with celiac disease and 26/100,000 person-years among controls, yielding an overall hazard ratio (HR) of 2.01 (95% confidence interval (CI), 1.64–2.47; P<0.0001). The risk of CDI was highest in the first 12 months after diagnosis of celiac disease (HR, 5.20; 95% CI, 2.81–9.62; P<0.0001), but remained high, compared to that of controls, 1–5 years after diagnosis (HR, 1.85; 95% CI, 1.22–2.81; P=0.004). Among 493 patients with CDI, antibiotic data were available for 251; there were no significant differences in prior exposures to antibiotics between patients with celiac disease and controls.

Conclusions:

In a large population-based cohort study, patients with celiac disease had significantly higher incidence of CDI than controls. This finding is consistent with prior findings of higher rates of other infections in patients with celiac disease, and suggests the possibility of altered gut immunity and/or microbial composition in patients with celiac disease.

Silver Bridge crossing Colorado River. Part of Grand Canyon’s Bright Angel Trail.

Therapeutic Drug Monitoring for Vedolizumab

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A recent observational study (N Williet et al. Clin Gastroenterol Hepatol 2017; 15: 1750-7) provides some important information about where we are heading with regard to therapeutic drug monitoring (TDM) with vedolizumab (VDZ).

This study enrolled 47 consecutive patients with either Crohn’s disease (CD, n=31) or ulcerative colitis (UC, n=16). In those without a clinical response at week 6, an additional dose of 300 mg of VDZ was administered at week 10.

Key findings:

  • VDZ levels were higher in responders than in nonresponders, which is in agreement with previous studies ( (NEJM 2013; 369: 711-21, NEJM 2013; 369: 699-710)
  • A low therapeutic drug level as early as week 2 (<24.5 mcg/mL) and at the end of induction (week 6) (<18.5 mcg/mL) was associated with the need for drug optimization within 6 months in all patients
  • All patients with a level <19.0 mcg/mL at week 6, regained a secondary response after optimization at week 10.
  • The authors note that in the GEMINI trial, anti-VDZ antibodies were detected in 56 of 1434 patients (3.7%).  In this cohort, no anti-VDZ were detected using the same methods.

My take: Low trough levels of VDZ at week 6 are associated with the need for drug optimization/increased dosing.

Cytosponge for Eosinophilic Esophagitis

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A recent prospective study (DA Katzka et al. Am J Gastroenterol 2017; 112: 1538-44 -thanks to Ben Gold for this reference) provided more information regarding the potential utility of the cytosponge for eosinophilic esophagitis (EoE); the cytosponge has been studied for Barrett’s esophagus.

Background: 86 adult patients were recruited; 6 could not swallow sponge.  In the remainder, 105 procedures were performed comparing the cytosponge to standard endoscopic biopsies. The cytosponge technique can be completed in ~5 minutes without sedation. “All that is required is centrifuging the cytosponge specimen in its preservative to create a pellet followed by routine paraffin embedding and processing.”

Key findings:

  • Cytosponge was considered to have adequate specimen in 102 of 105 cases, compared with 104 of 105 with endoscopic sampling
  • Using a cutoff of <15 eos/hpf for inactive disease, the authors found that the cytosponge had a sensitivity of 75% and a specificity of 86%.
  • Six patients had active EoE on cytosponge with negative endoscopic biopsies.
  • 14 patients with active EoE with endoscopic biopsies had <15 eos/hpf with cytosponge
  • No complications were noted with cytosponge.

The sensitivity of 75% is likely due to inadequate contact between cytosponge and esophageal wall which could be related to technique, especially in those with a normal caliber esophagus.

My take: The cytosponge appears to identify active EoE in the majority of adult patients.  In those with abnormal cytosponge, the likelihood of active EoE would be very high; as such, it could be a useful biomarker.  It is still probable that many with normal cytosponge result would need endoscopy due to suboptimal sensitivity.

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NEJM 2017; 377: e22. In this patient with lingual papillomas, hx/o melenoma, and both hyperplastic and adenomatous polyps, a genetic mutation identifying Cowden syndrome was identified.

Fatty Acid Intake and Risk of Ulcerative Colitis Flare

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A recent study (Barnes EL et al. Clin Gastroenterol Hepatol 2017; 15: 1390-6) found an association between the intake of certain fatty acids and the risk of an ulcerative colitis flare.  This is nicely summarized in the AGA Journals Blog.

Here’s the link: Does Consumption of Certain Fatty Acids Increase Risk of Ulcerative Colitis Flares?

Here’s an excerpt:

Diets with high levels of fatty acids such as myristic acid (found in palm oil, coconut oil, and dairy fats) increased risk of flare in patients with ulcerative colitis (UC), researchers report in the September issue of Clinical Gastroenterology and Hepatology. Their findings, from a prospective study of more than 400 patients in remission during treatment with aminosalicylates, could guide future studies of supplements or compounds that reduce risk of flares in patients with UC in remission…

Edward L. Barnes et al performed a prospective study of dietary patterns among 412 patients, from 25 sites, with UC in remission during monotherapy with an aminosalicylate (mesalamine, sulfasalazine, or balsalazide for at least 3 months before enrollment). Patients completed a validated food frequency questionnaire (on consumption of dairy, fruits, vegetables, eggs, meat, fish, cereals, breads, and starches, beverages, sweets, and baked goods) at enrollment and were followed for 12 months…

Forty-five patients (11%) had a relapse of UC within 1 year of study enrollment… In multivariable analysis, higher intake of myristic acid (odds ratio, 3.01) and alpha linolenic acid (odds ratio, 5.50) were associated with increased risk of relapse, although a dose–response relationship was retained only for myristic acid intake.

Other foods previously implicated in flares of UC, such as processed meat, alcohol, and foods high in sulfur, were not associated with an increased risk of flare.

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From Andy Warhol Exhibit at the High Museum

Costs of Biologics for Inflammatory Bowel Disease

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A recent study examines the market share and costs of biologic therapies for inflammatory bowel disease:

Excerpt from abstract:

The average biologic-taking patient accounted for $25 275 PMPY in 2007 and $36 051 PMPY in 2015. The average paediatric biologic-taking patient accounted for $23 616 PMPY in 2007 and $41 109 PMPY in 2015. In all patients, the share of costs for biologics increased from 72.9% in 2007 to 85.7% in 2015 (81.7% in 2007 to 94.9% in 2015 in paediatrics).

Conclusion

The vast majority of costs allocated to out-patient IBD medications in the USA is attributed to increasing use of biologic therapies despite the relative minority of biologic-taking patients.

My take: Biologic therapies are costly but also very effective.

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The Original Anti-TNF Therapy: Thalidomide

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A recent study (M Lazzerini et al. Clin Gastroenterol Hepatol 2017; 15: 1382-9) used data from 2 multicenter trials of 70 children to assess the efficacy of thalidomide in pediatric patients with refractory inflammatory bowel disease (37 with Crohn’s disease, 23 with ulcerative colitis)

Key findings:

  • 42 patients (60%) had clinical remission & 45 (64%) had clinical response at week 8
  • 38 patients (54%) had clinical remission or response at week 52. 29 of these patients had mucosal healing (no erosions or ulcerations) & 20 patients had histologic healing
  • 7 patients dropped out from study prior to 52 weeks due to side effects (n=5) or clinical relapse (n=2)

My take: I have not used thalidomide therapy and remain concerned about long term side effects (eg. peripheral neuropathy).  Though, the authors are correct that its safety “may be acceptable compared with the safety of other” treatments, especially if there are few remaining options.

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Will We Still Need Liver Biopsies to Diagnose Biliary Atresia in a Few Years?

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A recent study (C Lertudomphonwanit, R Moura, L Fei, Y Zhang, S Gutta, L Yang, KE Bove, P Shivakumar, JA Bezerra. Sci Transl Med. 2017; 9: eaan8462) may change how we diagnose biliary atresia (BA) and provides an insight into potential pathogenesis. Link to study: Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia

Using large-scale proteomics, the authors screened 1129 proteins in a discovery cohort (n=70) of patients with BA.  They identified several proteins that were increased with BA. Matrix metalloproteinase-7 (MMP-7) was the lead biomarker.  Subsequently, they used two additional validation cohorts.  Human subjects were infants in enrolled in the Prospective Database of Infants with Cholestasis (PROBE) which is part of the NIDDK-funded ChiLDRen (www.childrennetwork.org).

Key findings:

  • 76 proteins were significantly overexpressed or underexpressed in BA compared with children with intrahepatic cholestasis (IHC).
  • MMP-7 was more accurate than gamma glutamyltranspeptidase (GGT).  The combination of MMP-7 and GGT had a AUROC of 0.94 in validation cohorts.
  • The authors further studied the role of MMP-7 by immunostaining and found it primarily was detected in cholangiocytes of intrahepatic bile ducts in infants with BA.  It was also identified in a few hematopoietic cells.
  • MMP-7 expression in the liver did not correlate with fibrosis.
  • MMP-7 serum levels increased in neonatal mice after bile duct epithelial injury induced by intraperitoneal rotavirus administration.
  • Using a mice model, they found that a MMP-7 inhibitor (batimastat) could block the development of BA in a mouse model (in 86% of cases) compared with 0% in control mice.
  • Overall, the authors note that coupled with GGT, MMP-7 serum levels result in “sensitivity and specificity of 97 and 94% respectively, at optimal cutoff, which provided positive and negative predictive values of 85 and 99% respectively, if one considers the prevalence of BA of 25.9% among infants with conjugated hyperbilirubinemia.”

My take: More work is needed.  However, these values suggest that MMP-7 and GGT combined may be more accurate than a liver biopsy in the diagnosis of BA.

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South Kaibab Trail, Grand Canyon