Category Archives: Pediatric Gastroenterology Intestinal Disorder

Briefly Noted: Inflammatory Bowel Disease Updates

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Gut Microbial Diversity is Reduced in Smokers with Crohn’s Disease. JL Opstelten et al. Inflamm Bowel Dis 2016; 22: 2070-77.  This study compared stools from 21 nonsmoking patients with Crohn’s disease (CD) with 21 smokers with CD.  Smoking was accompanied by a reduced relative abundance of multiple genera.  My take: It is unclear whether smoking’s effect on the microbiome directly contributes to worsened outcomes or whether the changes in the microbiome are only an epiphenomenon.  Regardless, smoking increases the likelihood of worse outcomes in CD.

A Systematic Review on Infliximab and Adalimumab Drug Monitoring Levels, Clinical Outcomes and Assay. F Silva-Ferreira et al. Inflamm Bowel Dis 2016; 22: 2289-2301. This review selected 20 studies from an initial query of 1654 articles. Key points:

  • Different studies are difficult to compare due to distinct assays with different limitations. Thus, specific cutoffs are based on the specific assay used.
  • The authors state that proactive monitoring may be helpful at week 6, 14, 30 and 54 for infliximab.  They recommend checking infliximab level and antidrug antibodies in those with loss of response, mucosal ulceration or elevated biomarkers (eg. CRP, Fecal calprotectin).

Molecular Panels for Identifying Etiology with Acute GI Symptoms

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A recent study (MR Nicholson et al. J Pediatr 2016; 176; 50-6) examined the use of multiplex molecular testing to determine the etiology of acute gastroenteritis in children.  It is interesting that little has been published about this increasingly common practice of sending a 12 to 15 panel PCR assay when faced with acute GI symptoms, mainly diarrhea.

This study was a prospective population-based study of children <6 years with acute gastroenteritis (2008-2011).

Findings:

  • 70.4 % (152/216) samples tested positive for a pathogen, with norovirus the most frequent (n=78, 36.1%). Clostridium difficile was next at 16.2% (n=35).
  • 22.7% (n=49) tested positive for more than 1 pathogen including 25 with a C difficile detection
  • In this study, the authors noted C difficile colonization in 8% of healthy children aged 0-51 months and in 14% of children <12 months

Implications of this study and this technology:

  • Prior to this technology, traditional approaches typically identified less than 15% of the cases of acute gastroenteritis.  Thus, this new technology increases the likelihood of a definitive diagnosis.
  • Multiple pathogens, particularly with C difficile, illustrate how this new technology will present some difficulties with interpretation.  C difficile has very high rates of colonization in infants (anywhere from 25-80%) without AGE symptoms and lower rates of colonization in toddlers.  High colonization/detection has been noted in inflammatory bowel disease patients (17%) and pediatric oncology patients (30-55%).
  • For C difficile, molecular testing is much less likely to correlate with clinical disease than toxin-based assays. “A recent study in adults found that virtually all CDI-related complications occurred in patients with a positive toxin immunoassay.” (JAMA Intern Med 2015; 175: 1792-801)

My take: These panels are helpful in identifying infectious etiologies of AGE and may help prevent unnecessary endoscopic procedures.  Due to their limitations, careful selection of which patients to test and cautious interpretation of the results are needed.

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Sunset from Bar Harbor, ME

Sunset from Bar Harbor, ME

Increased Intestinal Blood Flow with Bolus Feedings in Very Low Birth Weight Infants

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From Journal of Pediatrics:  V Bozzetti et al. DOI: http://dx.doi.org/10.1016/j.jpeds.2016.05.031

Abstract:

Objective

To detect changes in splanchnic perfusion and oxygenation induced by 2 different feeding regimens in infants with intrauterine growth restriction (IUGR) and those without IUGR.

Study design

This was a randomized trial in 40 very low birth weight infants. When an enteral intake of 100 mL/kg/day was achieved, patients with IUGR and those without IUGR were randomized into 2 groups. Group A (n = 20) received a feed by bolus (in 10 minutes), then, after at least 3 hours, received the same amount of formula by continuous nutrition over 3 hours. Group B (n = 20) received a feed administered continuously over 3 hours, followed by a bolus administration (in 10 minutes) of the same amount of formula after at least 3 hours. On the day of randomization, intestinal and cerebral regional oximetry was measured via near-infrared spectroscopy and Doppler ultrasound (US) of the superior mesenteric artery was performed. Examinations were performed before the feed and at 30 minutes after the feed by bolus and before the feed, at 30 minutes after the start of the feed, and at 30 minutes after the end of the feed for the 3-hour continuous feed.

Results

Superior mesenteric artery Doppler US showed significantly higher perfusion values after the bolus feeds than after the continuous feeds. Near-infrared spectroscopy values remained stable before and after feeds. Infants with IUGR and those without IUGR showed the same perfusion and oxygenation patterns.

Conclusion

According to our Doppler US results, bolus feeding is more effective than continuous feeding in increasing splanchnic perfusion.

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Iceberg Lake, Glacier Natl Park

Iceberg Lake, Glacier Natl Park

FDA Gives Ustekinumab (Stelara) Approval for Crohn’s

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Here’s a link summarizing FDA approval: Medscape: FDA Clears Ustekinumab (Stelara) for Crohn’s Disease

An excerpt:

The US Food and Drug Administration (FDA) has approved ustekinumab (Stelara, Janssen Biotech, Inc) for the treatment of moderately to severely active Crohn’s disease in patients aged 18 years or older.

Specifically, the interleukin-12/23 inhibitor is indicated for Crohn’s patients who have failed or were intolerant to immunomodulator or corticosteroid therapy but who never failed treatment with a tumor necrosis factor (TNF) blocker or who failed or were intolerant to treatment with one or more TNF blockers, according to a company news release.

Ustekinumab is already approved in the United States for treatment of patients with plaque psoriasis and psoriatic arthritis…The clinical development program for ustekinumab for Crohn’s disease included more than 1300 patients across three pivotal phase 3 studies, which served as the primary basis for FDA approval.

In clinical studies of patients who were either new to, experienced with, or failed anti-TNF therapy, between 34% and 56% of patients experienced symptom relief in the 6 weeks after receiving a one-time intravenous induction dose of ustekinumab. “Noticeable improvement was observed as early as 3 weeks,” the company said.

Most patients who responded to induction dosing and who continued ustekinumab treatment with subcutaneous maintenance doses every 8 weeks were in remission at the end of 44 weeks (52 weeks from initiation of the induction dose), the company said.

Full prescribing information and a medication guide are available online.

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Small Pediatric IBD Studies …Briefly Noted

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G Wahbeh et al. JPGN 2016; 63: 348-51.  This retrospective case series with 4 children  (aged 12-17 years) indicated that 2 had a ‘clinical response’ to ustekinumab therapy, though one of these had ongoing elevation of CRP.  The dosing may have been too low: 90 mg at week 0 and 4, then every 8 weeks.  My take: This study shows that ustekinumab’s use in pediatric IBD seems to be a ‘shot in the dark’ given the lack of coherent data.

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L Zimmerman et al. JPGN 2016; 63: 352-56. Among a cohort of 123 children who had underwent a bowel resection, from 1977-2011, the overall postoperative complication rate was 13%.  This included 3 of 24 who had prior infliximab and 9 of 99 who had not received infliximab. It is noteworthy that the infliximab group had more corticosteroid exposure. The authors concluded that preoperative infliximab was not associated with increased complications but noted that their sample size was small. My take: Studies of adults with Crohn’s disease have yielded conflicting results on whether preoperative infliximab increases the risk of complications.  This study shows that children likely have a lower rate of postsurgical complications and more pediatric specific data are needed.

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From KT Park’s Twitter Feed:

calprotectin

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Latest on Tofacitinib for Refractory Ulcerative Colitis

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From Gastroenterology & Endoscopy News July 2016: Tofacitinib Effective in Refractory and Severe UC

An excerpt:

Tofacitinib (Pfizer), an oral agent already approved for certain patients with rheumatoid arthritis, can induce clinical remission in up to 25% of individuals with moderate to severe, refractory ulcerative colitis (UC) and clinical response in as many as 60% of these patients.

The results, based on two placebo-controlled trials involving more than 1,100 patients, showed the drug also increased the risk for serum lipid elevations but was otherwise safe. Researchers presented the data at the 2016 annual meeting of the European Crohn’s and Colitis Organization (ECCO; oral presentation 019)…

The new data are from the OCTAVE Induction 1 and Induction 2 trials, identically designed, randomized, double-blind and placebo-controlled Phase III studies…In the OCTAVE 1 trial, 476 patients received 10 mg of tofacitinib orally twice daily for eight weeks and 122 received an oral placebo. In OCTAVE 2, 429 and 112 patients were randomized to receive the two regimens, respectively.

Screenshot from gastroendonews.com

Screenshot from gastroendonews.com

Also from Gastroenterology & Endoscopy News August 2016: Update on Diagnosis and Treatment for Ulcerative Colitis  This article provides a succinct summary regarding diagnosis and treatments of ulcerative colitis; treatments discussed include emerging therapies like tofacitinib.

 

What to Make of A Motility Study of Children with Orthostatic Intolerance

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While a recent study (A Darbari et al JPGN 2016; 63: 329-35) provides some interesting data regarding the potential origin of gastrointestinal symptoms in the setting of orthostatic intolerance, I cannot support their conclusion that antroduodenal manometry (ADM) “should” be part of the evaluation of these affected children.

Background:

  • Retrospective study which included only subjects with a positive tilt test

What’s interesting:

  • Among 35 children with orthostatic intolerance due to either neurally mediated hypotension (NMH) or postural orthostatic tachycardia syndrome (POTS), ADM was abnormal at baseline or during tilt table testing in 26 (75%).
  • ADM studies were more often abnormal than gastric emptying studies, which were normal in 12 or 25.
  • Specific findings included neurogenic intestinal dysmotility in 15, antral hypomotility in 4, visceral hyperalgesia in 2, and regurgitation in 5.
  • GI symptoms of nausea, abdominal pain or vomiting were reproduced during tilt testing in 31 of 35 patients (89%).

Based on the discussion, the authors imply that ADM testing could help determine if the symptoms are due to neurogastrointestinal pathology or if normal, could indicate a central origin for the GI symptoms.  Thus, they conclude that motility testing “should” be part of comprehensive” orthostatic intolerance evaluation.

I would argue that this study does not show that ADM testing can reliably distinguish whether symptoms are due to a neurogastroenterological pathology or central pathology. And, in fact, there are better tests to examine for central origin.  I wouldn’t be surprised if many of their subjects had brain imaging, though this is not reported.

In addition, the authors acknowledge that ADM testing may not influence therapeutic decisions.  “The clinical response to promotility agents in children with POTS is generally low.”

My take: This study provides a useful mechanistic explanation of symptoms associated with orthostatic intolerance.  However, “I’m not there yet” on supporting ADM for all children with OI.

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Avalanche Creek Lake, Glacier Natl Park

Avalanche Creek Lake, Glacier Natl Park