Category Archives: Pediatric Gastroenterology Intestinal Disorder

More Lessons in TNF Therapy (Part 1)

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More data has been published regarding postoperative therapy with infliximab (IFX) in Crohn’s disease (Clin Gastroenterol Hepatol 2014; 12: 1494-1502, editorial 1503-6).

In this prospective, open-label study with at least 5 years of followup, 24 patients who were previously randomly assigned to receive IFX or placebo for 1 year after ileocolonic resection were given the option of continuing IFX or stopping IFX (“watch and wait approach”).  This was a strange study and perhaps mirrors clinical experience in that consistent usage of IFX was not maintained in the majority; in addition, there was not a set pattern with regard to thiopurine usage.

Of 11 patients who received IFX during the first year after surgery, 8 elected to stop IFX and all 8 experienced endoscopic recurrences at a mean of 18.2 months, including 5 who needed surgery.  Of 13 patients who received placebo during the first year after resection, 12 elected to initiate IFX at 1-year entry point;  7 of those responded with endoscopic remission. Overall, the mean percentage of time that a patient received IFX was similar between those initially assigned to IFX or placebo (50.3% vs. 53%).

Key findings:

  • Among those originally assigned to the IFX group, there was a longer mean time to first endoscopic recurrence (1231 days vs. 460 days in placebo group).
  • Colonoscopy identified recurrent disease in 22.2% of patients receiving IFX compared with 93% off IFX.  That is, throughout the study there were 84 colonoscopies.  If one was receiving IFX at the time of the colonoscopy, the adjusted rate ratio for being in remission while on IFX was 13.47.
  • Among patients who received IFX for at least 60% of the full study period, they had fewer surgical recurrences: 20.0% compared with 64.3% (5 of 8).
  • Recurrence was similar for patients receiving IFX monotherapy or in combination (though small numbers preclude a definitive assessment).
  • None of the three patients who continued IFX from the beginning have required an operation in the past 8 years.

One can speculate that the main reason why so many placebo-treated patients (12 of 13) elected to start IFX was that there was evidence of recurrent disease; conversely, many of the patients who received IFX postoperatively were in remission and opted for a watch-and-wait approach subsequently.

Study limitations: small numbers, open-label design, changes in therapy at patient’s physician discretion, and no restrictions on use of concomitant medications.

The associated editorial recommends the use of IFX postoperatively in high-risk patients (perforating disease, smokers, >1 surgical resection) and notes that therapy should be started 2-4 weeks after surgery because IFX is “less effective in preventing medical recurrence if started after endoscopic recurrence.”  The editorial suggests that low-risk patients should undergo a 6- to 12-month endoscopic evaluation.  Though, “we urgently need data from large prospective studies such as the PREVENT trial” (NCT01190839) as well as the POCER study.

Bottomline: Infliximab, administered within 4 weeks of an ileocolonic resection, reduces postoperative recurrence of Crohn’s disease and helps prevent further surgeries.  Studies (like this one) with long followup are essential to determine the effectiveness of anti-TNF (tumor necrosis factor) therapies.  It remains unclear whether only “high-risk” patients should receive anti-TNF therapy or whether these agents should be used more broadly.

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ImproveCareNow Video

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A recent (short ~2:30) ImproveCareNow (ICN) Video explains how ImproveCareNow is a forward-thinking network and how it has the potential to lead to better outcomes for children with inflammatory bowel disease.

If you are part of ICN, this video may help explain to your patients what ICN is all about.

Pattern of Skin Reactions to Anti-TNF Agents

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A recent study indicated a high rate of skin reactions to anti-TNFα in their pediatric inflammatory bowel disease (IBD) population (Inflamm Bowel Dis 2014; 20: 1309-15).

In a two-year prospective study, 84 children with IBD (64 with Crohn’s) who were receiving infliximab infusions were screened for skin changes and had labwork (blood tests and stool calprotectiin).

Key findings:

  • 40 (47.6%) had chronic skin reactions and half of these were considered severe. However, when looking at the “severe” lesions shown in Figure 2, one might question the characterization.
  • Ear lobes and scalp were affected most frequently with psoriasis-like manifestations, followed by eyelids, perioral and pubic areas, trunk, and extremities.
  • Skin reactions were more common in those with a low degree of intestinal inflammation based on calprotectin levels: 133 mg/g in those with skin changes compared with 589 in those without.
  • Seven patients (8.3% of entire cohort) discontinued therapy due to skin reaction.
  • Most patients responded well to topical potent corticosteroids.

Take-home message: In this prospectively-followed cohort, there was a surprisingly high rate of skin reactions.  In patients receiving anti-TNFα therapy, it is a good idea to look closely at their ears and scalp.

Related blog post:

TNF Antagonists and Psoriasis | gutsandgrowth

Is a Continuous IV Proton Pump Inhibitor Really Necessary for GI Bleeders?

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A recent systemic review and meta-analysis (JAMA Intern Med. doi10.10001/jamainternmed.2014.4056) calls into question the practive of using continous intravenous proton pump inhibitor (PPI) for high-risk bleeding ulcers.

“Current guidelines recommend an intravenous bolus dose of a proton pump inhibitor (PPI) followed by continuous PPI infusion after endoscopic therapy in patients wtih high-risk bleeding ulcers.  Substitution of intermittent PPI therapy, if similarly effective as bolus plus continous-infusion PPI therapy, would decrease the PPI dose, costs, and resource use.”

Ultimately, only randomized 13 studies (Table 1) were identified that examined only high-risk ulcers, and used appropriate treatment protocols.  Table 2 lists the results with regard to recurrent bleeding, mortality, surgery, blood transfusions, and length of hospital stay as well as the number of patients; 1691 patients had data for rebleeding within 30 days.  Typically, intermittent PPI dosage was 40-80 mg BID.

Key findings:

  • There was not an increased risk of rebleeding with intermittent vs bolus-continuous; at 7 days, the risk ratio was 0.72 favoring intermittent treatment and the absolute difference was -2.64% (predefined noninferiority was a margin of 3%)
  • The absolute risk difference for all outcomes was less than 1.5% for all rebleeding outcomes.  Using the 95% confidence interval for absolute risk difference, the values were -0.28, 0.17, and 1.49for rebleeding within 7 days, 3 days, and 30 days.

Bottomline: this systemic review indicates that intermittent PPI therapy may be similarly effective as continuous drip PPI for meaningful outcomes in high-risk bleeding ulcers.

Related blog post:

All bleeding stops | gutsandgrowth

Accuracy of ENT diagnosis of Reflux Changes

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Many gastroenterologists suspiciously view a diagnosis of laryngopharyngeal reflux (LPR) as assessed by an Ear, Nose, and Throat (ENT or otorhinolaryngologist) physician.  This is due to a high degree of variability of these visible findings in a number of studies.  A recent pediatric study reaches the same conclusion (J Pediatr 2014; 165: 479-84).

In this study, the authors recruited 52 infants in an effort to establish a reflux finding score for infants (RFS-I).  This infant scale was modified based on a previous RFS developed in adults (Laryngoscope 2001; 111: 1313-7).  In these infants, scored videos were evaluated by 3 pediatric ENTs, 2 adult ENTs, and 2 gastroenterology fellows.

Specific finding:

  • “laryngeal erythema/edema showed the lowest observer agreement…it is often speculated that laryngeal edema is caused by LPR, but no convincing evidence is available to support this theory.”

Bottomline: “Only moderate interobserver agreement [of the RFS-I] was reached with a highly variable intraobserver agreement…the RFS-I and flexible laryngoscopy should not be used solely to clinically assess LPR related findings of the larynx, nor to guide treatment.”

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Reducing Diagnostic Uncertainty in Hirschsprung’s Disease

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Previously this blog noted the emergence of calretinin immunohistochemisty (What is calretinin? | gutsandgrowth).  Now, more data has been published indicating that calretinin reduces inconclusive rectal biopsies for the diagnosis of Hirschsprung’s disease (JPGN 2014; 58: 603-07).

The authors analyzed data retrospectively for 45 patients prior to the use of calretinin and 42 patients after calretinin introduction.

Key finding: 37.8% (17 of 45) of patients had inconclusive rectal biopsies prior to use of calretinin compared with 11.9% (5 of 42) after including calretinin immunohistochemistry.

Clinical Features of 22q11.2 Deletion Syndrome

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Since I participate in the 22q Specialty Clinic in Atlanta, I am interested in relevant clinical studies.  A recent study provides more information on clinical features and follow-up (J Pediatr 2014; 164: 1475-80).

This retrospective and prospective multicenter study involved 228 patients.  The median age at diagnosis was 4 months.  In 71% the diagnosis was made before age 2 years and predominantly related to congenital heart disease and neonatal hypocalcemia.

Key findings:

  • The survival probability was 0.92 at 15 years from diagnosis, most commonly from severe cardiovascular complications.  Two subjects died without cardiac defects, one with severe autoimmune anemia and the second with lymphoproliferative disease.
  • Congenital heart disease was confirmed in 79% of the entire cohort.
  • Neonatal hypocalcemia was noted in 43%
  • ENT manifestations were present in 59% and included most commonly velopharyngeal insufficiency
  • GI manifestations were noted in 41%, particularly feeding difficulties in infancy.  Anorectal malformations were identified in 5% and esophageal atresia was noted in 1%.  GI problems tended to improve during followup, particularly gastroesophageal reflux.  During followup, three children with abdominal pain (along with leg pain) had mild hypocalcemia.
  • Autoimmune manifestations developed in 11%, most commonly autoimmune thrombocytopenia.

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Link: Practice guidelines for 22 q (from UC Davis Website and J Pediatr. 2011 Aug;159(2):332-9.e1. doi: 10.1016/j.jpeds.2011.02.039).

Understanding Resistance to Helicobacter pylori

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An editorial (by Ben Gold -congratulations!) helps sort out the potential advantages of gene based testing for Helicobacter pylori in a commentary on a recent publication (JPGN 2014;  59: 6-9).

In the study, the authors used formalin=fixed biopsies in 38 H pylori--infected gastric biopsies.  These specimens were examined for 23S rRNA mutations associated with resistance to clarithromycin.  Overall, the authors (from Dallas, TX) noted H pylori in 4.5% of their biopsies.  The majority of these children, treated between 2010-2012, were given clarithromycin, amoxicillin, and a proton pump inhibitor (n=25).  Due to clarithromycin resistance, this is no longer considered a first-line treatment in the absence of clarithromycin susceptibility testing according to NASPGHAN guidelines (published in 2011).

The authors noted a cure rate of 62.5%, likely due to the use of clarithromycin-based triple therapy.  In addition, Dr. Gold notes that the authors identified a very high rate of clarithromycin resistance (50%): “greater than that reported by any of the previously published national surveys or single-center studies in the United States, Europe, or Japan.”

Take-home point from Dr. Gold: “Because the common mutations responsible for H pylori resistance to the other major antimicrobials used for eradication…have been described, the assay developed by Mittui et al could be modified to include a panel of antibiotics…to optimize therapy.”

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Higher Doses of Topical Steroids for Eosinophilic Esophagitis

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A recent randomized, double-blind, placebo controlled study (Gastroenterol 2014; 147: 324-33) examined “high-dose” fluticasone propionate (FP) for patients, aged 3-30 years, with eosinophilic esophagitis (EoE).  FP patients received 1760 mcg divided into two doses for three months, then the dose was reduced in half.

Efficacy: Among the 28 FP patients, a complete remission (CR) (≤1 eosinophil/hpf on histology) was evident in 65% compared with 0% CR in 14 placebo patients.  Furthermore, partial response (PR) (multiple definitions of responsiveness -see Figure 2) evident in about 75%.  Reduction in dose to 880 mcg/day resulted in 93% of EoE participants maintaining CR or PR.

Molecular response: The authors also studied the transcriptome prospectively in these patients with the “Eosinophilic esophagitis diagnostic panel” (EDP). “A large portion of the participants receiving FP in phase 1 showed a normalized signature compared with the dysregulated screening and placebo signatures….notably, the 6 FP participants with histologic PR or no remission also had a partial reversal with a signature different from the placebo group…However, there were still a few molecular nonresponders whose signatures failed to normalized upon FP treatment.”

Based on their study findings: the authors recommend assessment at 3 months after initiation of topical steroids because “extending the timeframe for high-dose FP to 6 months does not increase remission status.”

The authors could not identify any demographics or signs/symptoms that predicted response to high-dose FP. In addition, in this small cohort, no difference in adverse effects compared to placebo were found.

My take on this study is that it raises more questions than it answers.

  • Is the higher induction dose of FP really needed or would 880 mcg/day over a 6 month period result in the same findings?
  • Is FP superior to budesonide which is considered to have less systemic absorption?
  • Should we be using higher doses of budesonide as well?
  • Would patients be better off receiving systemic steroids and transitioning to topical steroids?
  • What are the long-term consequences, good and bad, in using higher steroid doses?

Take-home message: In a carefully designed study with molecular correlation, higher doses of Fluticasone achieved high rates of complete remission in EoE patients.  Except for elemental diets, no dietary therapies have shown to have a higher response rate.

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