Category Archives: Pediatric Gastroenterology Intestinal Disorder

Use of Gluten-Free Diet with Inflammatory Bowel Diseases

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As noted in a previous blog (The Search for a Dietary Culprit in IBD | gutsandgrowth), alternative diets have been explored both for symptom improvement and in efforts to improve inflammation in individuals with inflammatory bowel diseases (IBD).  A new study from North Carolina indicates that nearly 20% of patients have tried a gluten-free diet (GFD) to help control clinical symptoms in IBD (Inflamm Bowel Dis 2014; 20: 1194-97).

While adoption of a GFD clearly is effective for celiac disease, it has become popular, along with a low FODMAPs diet, as an alternative treatment for irritable bowel syndrome (IBS)/and “non-celiac gluten sensitivity.”  Since IBS is a common comorbidity with IBD (see recent blog: New Biomarker for Crohn’s Disease (Plus Two …), it is not surprising that a GFD would be used by some with IBD.  In this study, the authors performed a cross-sectional study using a GFD questionnaire in 1647 IBD patients though a CCFA longitudinal internet-based cohort.

Results:

  • 19.1% had previously tried a GFD and 8.2% reported current use of GFD.
  • 65.6% described improvement while on a GFD.  Improved symptoms included fatigue, nausea, bloating, abdominal pain, and diarrhea.
  • 0.6% of patients reported a concurrent diagnosis of celiac disease (which is similar to overall celiac prevalence in U.S.)

Given the structure of this study, which is mainly an internet survey, there are many limitations in its interpretation.  Certainly, this study does not prove that a GFD is effective for IBD.  However, it is clear that a GFD is used frequently and may improve IBD/IBS symptoms.

Take-home message: Particularly in patients who have ongoing symptoms despite  mucosal healing, pursuing either a low FODMAPs diet or a GFD may be helpful.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects), implementation of diets and specific medical management interventions should be confirmed by prescribing physician.  Application of the information in a particular situation remains the professional responsibility of the practitioner.

Pushback on Probiotics

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I had not paid much attention to a study last year (Lancet 2013; 382: 1249-57) titled, “Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhea and Clostridium difficile diarrhea in older patients (PLACIDE): a randomized, double-blind, placebo-controlled, multcentre trial.”

A useful review (Gastroenterol 2014; 146: 1822-23) of this study provides some useful insight into the use of probiotics.  The authors state that “in the last decade, medical and non medical professionals have endorsed the use of probiotics as a means of preventing AAD through a dogma that adding ‘good bacteria’ will prevent dysbiosis caused by ‘bad bacteria.'”  They note that several meta-analysis have supported a positive benefit for probiotics in this setting; yet, the “results merit cautious interpretation owing to a high risk of bias and notable heterogeneity of included studies.”

The PLACIDE study overcomes many of the previous limitations in this well-designed study design which enrolled a large cohort of 2,981 patients (≥65 years old).  The probiotics used in this trial were lactobacillus acidophilus along with bidodbacterium bifidum and lactis.  Ultimately, “patients receiving probiotics were as likely to develop AAD as patients in the placebo arm (relative risk 1.04).”  The rate of C difficile infection was ~1% and lower than expected.

While this study did not demonstrate any benefit from probiotics, there was no significant harm identified from probiotics; though, patients receiving probiotics were more likely to develop flatus and bloating in comparison to placebo.

Take-home message: “This study now also points away from probiotics being of benefit…probiotics use will not diminish as a result of this trial.  Parties will, argue rightly or wrongly, that the wrong strains were chosen…However, what the PLACIDE trial does point is that there is no clear evidence for use of probiotics in this setting until high-quality RCTs are conducted.”

Another probiotic reference:

JAMA Pediatr 2014; 168: 228-33.  This randomized double-blind, controlled trial conducted in 9 neonatal units in Italy compared L reuteri DSM 17938 to placebo for prevention of colic.  Mean duration of daily crying was 38 min in probiotic group compared with 71 min in placebo-treated patients, though these measures were with a nonvalidated diary.  Conclusions of authors: “prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the magnitude of crying and functional gastrointestinal disorders.”

Related blog posts:

Clostridium difficile Epidemiology

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A recent study shows that Clostridium difficile infection (CDI) is identified frequently in young children and that approximately three-fourths had recent preceding antibiotics (Pediatrics 2014; 133: 651-58). Abstract link.

Methods: “Data from an active population- and laboratory-based CDI surveillance in 10 US geographic areas during 2010–2011 were used to identify cases.”

Key findings:

  • Of 944 pediatric CDI cases identified, 71% were community-acquired
  • CDI incidence per 100 000 children was highest among 1-year-olds (66.3)
  • Using a representative sample (n=84) who reported diarrhea on the day of stool collection, 73% received antibiotics during the previous 12 weeks.

Despite the frequency of CDI, understanding a couple of key diagnostic pearls is crucial. According to the American Academy of Pediatrics Committee on Infectious Disease policy guideline: (Link to AAP guideline PDF)

  • Recommends avoid routine testing in pediatric patients less than 1 year of age due to high carriage rates.
  • “Testing for C difficile can be considered in children 1 to 3 years of age with diarrhea, but testing for other causes of diarrhea, particularly viral, is recommended first>
  • “A common mistake is to… test for cure. C difficile, its toxins, and genome are shed for long periods after resolution of diarrheal symptoms.”
  • “An interval greater than 4 weeks since last testing should be used for testing with a recurrence.”

Bottomline: This most recent study reinforces the notion that about 1/4th of pediatric CDI occurs in the absence of recent antibiotics; nevertheless, understanding the limitations of testing for CDI could prevent a fair amount of aggravation.

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Not Much Data with Allopurinol

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The authors of a recent case report (JPGN 2014; 59: 22-24) note that there has been “only 1 study on the pediatric use of allopurinol in inflammatory bowel disease.”  A previous post on this blog has reviewed the use of allopurinol for IBD and provided several references –mainly from use in adults (Data on Allopurinol | gutsandgrowth).

This current study reports on three cases.  In all three cases the combination of allopurinol with low-dose 6-mercaptopurine resulted in clinical remission, including one patient which was poorly responsive to infliximab.  In all three cases, frequent thiopurine metabolites were obtained to help guide dosing.  Prior to allopurinol, all 3 patients had a 6-MMP/6-TG ratio >20; with use of allopurinol there was a decrease in this ratio.

Among these patients, one developed mild leukopenia which resolved with medication adjustment.

Bottomline: Allopurinol can be effective in optimizing thiopurine treatment, but need to be administered carefully.  More studies on its use are needed.

You Still Need the Data

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A recent study (J Pediatr 2014; 165: 23-9) confirmed the obvious: “early empiric antibiotic use in preterm infants is associated with lower bacterial diversity.”  That being said, you still need the data and the specific changes are of importance.

This study examined the stools from 74 preterm infants (≤32 weeks gestational age) and determined how the microbiota changed in relation to no antibiotics (18% of cohort), brief antibiotics (1-4 days) (64% of cohort), or ‘intensive’ antibiotics (5-7 days) (18% of cohort).  Empiric antibiotics consisted of ampicillin and gentamicin.  Stools were analyzed with the 16s ribosomal DNA community profiling.

The key findings are graphically shown in Figure 1 with pie charts showing the relative abundance of 10 bacterial genera at week 1, week 2, and week 3 in each of the three groups.

  • Those who received 5-7 days of antibiotics had the most changes in their microbiota with increased Enterobacter and lower bacterial diversity in the second and third weeks of life.
  • In those who received no empiric antibiotics there was increasing bacterial diversity noted sequentially.  These changes were not seen in either of the antibiotic groups. However, the group with brief antibiotic exposure returned to their baseline diversity by week 3.
  • Infants receiving early antibiotics experienced more cases of necrotizing enterocolitis, sepsis and death than those who were not exposed to antibiotics (this was not proven to be casually-related).

Take-home message: This study proves that antibiotics change the microbiome in neonates and that neonates exposed to antibiotics may have complications as a result.  Better biomarkers (with rapid turn around time) would allow more careful selection of which neonates need empiric antibiotics.

Related blog posts:

“We Still Have More to Learn”

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“The most beautiful thing we can experience is the mysterious, it is the source of all true art and science. He to whom this emotion is a stranger, who can no longer pause to wonder and stand rapt in awe, is as good as dead: his eyes are closed.” –Albert Einstein.

I’m not sure the above quote has much direct relevance to today’s blog, but it came to mind after reading “we still have more to learn” in a recent editorial.  The editorial elaborated on another study showing that hypotonic fluids increase the risk of hyponatremia (J Pediatr 2014; 165: 163-9, editorial 14-15).  The editorial cautions that “intravenous fluid therapy is a prescription much like antibiotics or chemotherapy.  What we prescribe for intravenous fluids must fit the patient’s history and condition.”

The article was a systemic review of published studies.  Though 1634 citations were screened, only 10 studies (n=893) were included as independent randomized controlled trials.  Hypotonic fluids were defined as tonicity <250 mmol/L; isotonic fluids were defined as normal saline (0.9%), Ringer lactate, Hartmann solution, and any other fluid with tonicity approaching that of normal serum. The key findings:

  • Hypotonic fluids increase the relative risk (RR) of hyponatremia (Na <135) with RR of 2.37
  • Moderate hyponatremia (Na <130) risk was increased further with RR of 6.1.
  • Sub-group analysis of half-normal saline showed relative risk for hyponatremia was 2.42.

The editorialists comment that much has changed in the 55+ years since Holliday and Segar’s publication in 1957 describing maintenance fluid requirements.  These changes include sicker patients who are at increased risk for non-osmotic ADH release.  Thus, even patients receiving isotonic fluids are at some risk for hyponatremia.  However, the key point is that maintenance fluids are not appropriate for replacement of losses and in the perioperative setting.

Bottomline: Think twice before using a hypotonic fluid especially on admission or after surgery.  While there is no perfect intravenous fluid for all patients at all times, in many patients, isotonic fluids will be more favorable by reducing the risk of hyponatremia.

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Unrelated link:

In Treating Crohn’s Disease, Earlier is Better | – AGA Journals Blog

Drug Therapy for Celiac Disease

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While a life-long gluten-free diet (GFD) is effective in most individuals with Celiac disease (CD), it is not effective in some. This could be related to cross contamination of food products, improper/inaccurate labeling and perhaps other factors as well.  As a consequence, there is a rationale for the development of medical therapy.  A recent study (Gastroenterol 2014; 146: 1649-58) has shown the ability of ALV003, a mixture of 2 recombinant gluten-specific proteases administered orally, to protect patients with celiac disease from gluten-induced mucosal injury in a phase 2 trial.

Methods: In a 6-week challenge study, adults with biopsy-proven celiac disease were divided into a treatment group with ALV003 (n=20) or a placebo group (n=21).  The 2.0 g gluten dose (equivalent to 1/2 slice of bread) for the study was determined after an optimization study (using 1.5 g, 3.0 g or 6.0 g of gluten (bread crumbs) in three divided doses).  Biopsies were taken before and after the gluten challenge.

Key finding:

  • No significant mucosal deterioration was observed in biopsies from the ALV003 group based on biopsies after the challenge period.  In contrast, the placebo group did have evidence of mucosal injury.

Related blog posts:

 

Putting in Place a Big Piece of the Eosinophilic Esophagitis Puzzle

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A recent study (Nature Genetics 2014; doi:10.1038/ng.3033 -thanks to Seth Marcus for this reference) provides novel in-depth molecular and mechanistic information on eosinophilic esophagitis (EoE).  Though the publication and supplemental material span only 8 pages, it is packed with information and highly technical assays and thus takes an effort to work through.

The authors performed a genome-wide association study (GWAS) of SNPs (single nucleotide polymorphisms) from >1.5 million genetic markers.  In total, this study involved samples from 736 EoE patients and 9246 controls. Four prominent markers were identified at 2p23, 5q22, 8p23, adn 15q13; however, the marker at 2p23 was most highly associated with a risk for EoE.  And, 2p23 included the CAPN14 gene (best SNP rs77569859).

Key Results:

  • CAPN14 is “specifically expressed in esophageal epithelium and is dynamically upregulated as a function of disease activity.”  Though CAPN14 is expressed in other tissues, it is primarily in the esophagus and pharynx (Figure 2).
  • CAPN14 encodes calpain 14, a calcium-activated cysteine protease.  CAPN14 showed the greatest upregulation in comparison to all members of the CAPN family.  Calpain proteases mediate protein cleavage for structural proteins, signaling molecules, transcription factors, and inflammatory mediators.  The latter are “germane for allergic responses.”
  • CAPN14 levels are >2-fold increase in individuals with active EoE.
  • CAPN14 gene is modified by IL-13.

Take-home message: (from the authors) This study shows the “potential centrality of CAPN14 in the etiology of EoE….We propose a model that links the interplay of allergic sensitization with an EoE-specific, IL-13-inducible esophageal response involving CAPN14.”

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Beauty is More Than Skin Deep

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A recent article discusses how a British model is an inspiration.  “Bethany Townsend made a bold move posting photos of herself in a bikini with colostomy bags on full display….Millions of people have seen her picture on the Crohn’s and Colitis UK page.”

If you want, take a look; here’s the link: British bikini model 

Childhood Salmonella and Development of Irritable Bowel

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“An analysis of children affected by a Salmonella enteritidis outbreak more than 20 years ago provides evidence that pathogen-induced gastroenteritis during childhood is a risk factor for irritable bowel syndrome (IBS) in adults. The findings from this long-term study are published in the July issue of Gastroenterology.”  This study (Gastroenterol 2014; 147: 69-77) is nicely summarized in a recent AGA Journal blog –here’s the link: What are the Long-Term Effects of Gastrointestinal Infections During Childhood.

Key point/excerpt:

Cesare Cremon et al. identified and monitored individuals affected by a foodborne Salmonella enteritidis outbreak that involved 1811 people in Bologna, Italy in 1994. The outbreak resulted from delivery of contaminated tuna sauce to 36 schools. Although some adult staff became ill, 93% of those affected were children, 3–10 years old…Sixteen years later, Cremon et al. evaluated the long-term effects of the outbreak, mailing a questionnaire to 757 subjects…Among exposed participants, 32.3% reported functional dyspepsia, compared with 27.1% of controls, and 36.8% reported having IBS, compared with 23.3% of controls. The odds ratio for IBS among people exposed to the Salmonella was 1.92.