Monthly Archives: September 2014

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.

 

Durability of Infliximab in Pediatric Crohn’s Disease

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Similar to a previous recent study (How Long Will Infliximab Work? | gutsandgrowth), another large retrospective review confirms that infliximab has sustained effectiveness in the majority of children with Crohn’s disease (CD) (Inflamm Bowel Dise 2014; 20: 1177-86).

This study examined a 195 patients with a median age of 13.9 years from the years 2000-2011. Key findings:

  • Based on physician global assessment and pediatric Crohn’s activity index ≤10, 81% experienced a complete response.  Only 40 patients had endoscopic reassessment.  Among the 22 of these patients considered to be in a complete response, 16 (73%) had complete mucosal healing.
  • Despite optimization (based on clinical symptoms) in 35%, complete responders experienced a loss of response at a rate of 2% to 6% per year over 5 years.
  • In this cohort, combination therapy with at least 30 weeks of immunomodulator therapy improved durability of response.  Since 2006, the authors indicate that “our preference has been to use concomitant methotrexant rather than thiopurines” in boys.
  • Infliximab was well-tolerated.  However, severe infusion reactions were noted in 5% at some time point, 8% had psoratiform skin lesions, and 24% had elevated ALT.
  • Clinical response to infliximab was associated with enhanced linear growth.

Take-home message (from the authors): “the clinical response and growth data presented argue in favor of early treatment.”

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“Silent” Crohn’s Disease

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David Binion comments on Silent Crohn’s Disease (CD) in a recent Gastroenterology & Hepatology: Here’s the link —Silent Crohn’s Disease

Key points:

  • “Approximately one-quarter of patients with active disease are asymptomatic.”  Some have termed these patients to have Silent CD.
  • Biomarkers including blood tests (eg. CRP), fecal markers (eg. Calprotectin), imaging and endoscopy can reveal active disease in many asymptomatic patients.  Conversely, about one-sixth of patients are “overreporters” who describe abdominal complaints without objective evidence of inflammation.
  • “CRP elevation represents a more significant threshold of mucosal damage compared with endoscopic assessment.”  “In our study, 37% of the silent Crohn’s disease cohort [with elevated CRP] at our center required hospitalization within 2 years compared with 7% of patients who felt well and had no elevation of CRP level.”

These findings reinforce the notion that mucosal healing in combination with symptoms is important at predicting long-term response to treatment.  A commonly-used physician global assessment may miss silent CD.

Bottomline: In those with “inactive” CD, obtaining a CRP (and possibly a fecal calprotectin) will improve detection of silent CD.

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Early Results of FMT for IBD -Any Efficacy?

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As more data emerges on fecal microbiota transplantation (FMT) for inflammatory bowel disease in well-designed trials, it is not clear if FMT will be effective.  A summary of some recent abstracts is available at this link to Gastroenterology and Endoscopy News: Fecal Transplants for IBD Show Mixed Results in Trials

One trial with 53 patients with mild to moderate UC (27 randomized to FMT, 26 to placebo) once weekly for six weeks showed similar results in both groups with 7 FMT patients and 8 placebo recipients experiencing improvement of at least 30% in their Mayo scores.  Dr. Lawrence Brandt said, “It may be that we need to look at the patient’s unique bacterial composition and determine which organisms need to be replaced and formulate FMT accordingly.”

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Methotrexate –First Choice Immunomodulator?

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In pediatric inflammatory bowel disease (IBD), there has been an uptick in the usage of methotrexate (MTX) over the last 10 years.  This coincides with malignancy concerns, particularly hepatosplenic T-cell lymphoma, with thiopurine use.  Recently, a retrospective study examines the use of MTX in a cohort of 290 patients from 19 centers. 172 received monotherapy with MTX for >3 months and had at least one year of followup.

Key findings:

  • 81 of these 172 used MTX as their first immunomodulator (IMM) (monotherapy) and this had become more prevalent towards the end of the study period (60% in 2010).  Among these 81, 27% achieved a sustained clinical remission –based on physician global assessment.
  • 35% who used MTX as their second IMM achieved a sustained clinical remission.
  • Among MTX users, 15% had increased ALT (>60 IU/L) and 12% had white blood cells <4000 cells/mL.
  • There was wide variation in usage of MTX therapy among different pediatric centers.
  • According to Figure 2, there was little difference in the usage of MTX between males and females.  Given the well-recognized teratogenicity with MTX, it is interesting that the authors did not elaborate on this finding.

One limitation of this study was the absence of data regarding route of MTX administration. Oral bioavailability is likely a little lower than with parental dosing.  Another limitation was reliance on physician global assessment without correlating a marker for mucosal healing.

Take-home message: Methotrexate is being used more frequently as a first-line IMM.  As there are no head-to-head comparison studies with thiopurines, one can only speculate whether its efficacy and safety are good enough to chosen as the first immunomodulator.

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Mechanism for FODMAPs diet

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According to a recent study (Gut doi:10.1136/gutjnl-2014-307264 -thanks to KT Park for reference), a low FODMAPs diet changes the microbiome which in turn may relate to improvements in patients with irritable bowel syndrome.

Abstract

Objective A low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols) diet reduces symptoms of IBS, but reduction of potential prebiotic and fermentative effects might adversely affect the colonic microenvironment. The effects of a low FODMAP diet with a typical Australian diet on biomarkers of colonic health were compared in a single-blinded, randomised, cross-over trial.

Design Twenty-seven IBS and six healthy subjects were randomly allocated one of two 21-day provided diets, differing only in FODMAP content (mean (95% CI) low 3.05 (1.86 to 4.25) g/day vs Australian 23.7 (16.9 to 30.6) g/day), and then crossed over to the other diet with ≥21-day washout period. Faeces passed over a 5-day run-in on their habitual diet and from day 17 to day 21 of the interventional diets were pooled, and pH, short-chain fatty acid concentrations and bacterial abundance and diversity were assessed.

Results Faecal indices were similar in IBS and healthy subjects during habitual diets. The low FODMAP diet was associated with higher faecal pH (7.37 (7.23 to 7.51) vs 7.16 (7.02 to 7.30); p=0.001), similar short-chain fatty acid concentrations, greater microbial diversity and reduced total bacterial abundance (9.63 (9.53 to 9.73) vs 9.83 (9.72 to 9.93) log10 copies/g; p<0.001) compared with the Australian diet. To indicate direction of change, in comparison with the habitual diet the low FODMAP diet reduced total bacterial abundance and the typical Australian diet increased relative abundance for butyrate-producing Clostridium cluster XIVa (median ratio 6.62; p<0.001) and mucus-associated Akkermansia muciniphila (19.3; p<0.001), and reduced Ruminococcus torques.

Conclusions Diets differing in FODMAP content have marked effects on gut microbiota composition. The implications of long-term reduction of intake of FODMAPs require elucidation.

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Low-FODMAPs with or without Gluten-Free Diet in IBS

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In a small study with 60 patients with irritable bowel syndrome (DDW abstract 374), the response rate to a Low-FODMAPs/Normal gluten diet was as effective as a Low-FODMAPs/Gluten-free diet.  Both diets were more effective in reducing abdominal symptoms than a normal diet.  A summary of this abstract from Gastroenterology & Endoscopy News: Nixing Gluten Offers No Added Benefit To Low-FODMAPs Diet for IBS

According to Lin Chang, MD: “The beneficial effect of low FODMAPs does not appear to be predominantly due to gluten avoidance.”

Related blog post: An Unexpected Twist for “Gluten Sensitivity” | gutsandgrowth