Category Archives: Pediatric Gastroenterology Intestinal Disorder

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.

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“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.

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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.

Omega-3 Fatty Acids, Lipid Emulsions, and Hepatic Pathology

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Many have advocated for the use of parenteral fish oil lipids like Omegaven which are rich in omega-3 polyunsaturated fatty acids (O3FAs), though the data in support of them are limited (New lipid emulsions — lacking data to support usage …).

A recent study (J Pediatr 2014; 165: 59-64) identified seven liver-inclusive intestinal transplants who had received O3FAs.   This retrospective review study took place between 2003-2012.  These seven patients had received O3FAs for a mean of 62% of their total life span before transplant.  While these patients almost all had resolution of cholestasis (mean total bilirubin 0.7 mg/dL at time of transplant), advanced fibrosis (stage 3 or 4) was noted on explant pathology.  The histologic inflammatory scores were lower (P=.056) in comparison to O6FA group.

The authors make several important points:

  • The “results provide additional evidence that the improvement in hyperbilirubinemia following O3FA substitution therapy does not consistently produce histologic recovery of the liver.”
  • This study does not address whether comparable improvements could have been obtained from lipid restriction among the O6FA group.
  • Only 1 of 20 studies of O3FA lipid emulsion in PNALD includes hepatic histopathology as an outcome measure.

This is not the first study that indicates that liver fibrosis may persist and progress on O3FA therapy (J Pediatr 2010; 156: 327-31, J Pediatr Surg 2010; 45: 95-9, JPGN 2013; 56: 364-9).

Bottomline: Continued investigation of O3FA emulsions in PNALD is needed and assessing liver histology may be needed prior to intestinal transplantation.

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Systemic Review of Dietary Treatments for Eosinophilic Esophagitis

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A recent analysis of the literature for dietary treatment of eosinophilic esophagitis (EoE) has been published (Gastroenterology 2014; 146: 1639-48). Only 33 references out of 581 screened were included, yielding 1317 patients (1128 children and 189 adults).

Key findings:

  • Elemental diets were effective in 90.8%
  • Six-food elimination diets were effective in 72.1%
  • Allergy test-directed diets were effective in 45.5%
  • Adults responded similarly to children to dietary interventions with remission in 67.2% compared to 63.3%.

Bottomline: This study reiterates the dietary response rates from multiple previous studies. The finding that adults respond similar to children is less well-recognized, perhaps because dietary treatments are used less often in adults with EoE.

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Tofacitinib -Risks and Benefits in Rheumatoid Arthritis

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Previously Tofacitnib, an oral Janus kinase inhibitor, has shown promise as an emerging treatment for inflammatory bowel disease (Tofacitinib –a JAK Inhibitor for UC | gutsandgrowth).  So, a recent large study in tofacitinib use in rheumatoid arthritis caught my attention, specifically with regards to the potential risks of treatment (NEJM 2014; 370: 2377-86).

This double-blind study randomly assigned 958 patients (mean age ~49 years) to receive 5 mg or 10 mg of tofacitinib twice daily or weekly methotrexate.  This study, called ORAL Start, examined the effectiveness of these drugs over a 24 month period in patients with active moderate-to-severe rheumatoid arthritis naive to therapeutic doses of methotrexate.

Key findings:

  • Among tofacitinib patients, 25.5% (5 mg group) and 37.7% (10 mg group) had an ACR 70 response at 6 months compared with 12.0% of methotrexate patients.  Results at 12 and 24 months were similar (Figure 1)
  • Adverse effects:
  1. 4% of tofacitinib patients developed herpes zoster compared with 1.1% of methotrexate patients
  2. 5 tofacitinib patients developed cases of cancer (three cases of lymphoma) compared with 1 case among patients receiving methotrexate
  3. Tofacitinib was associated with decreases in neutrophil/lymphoctye counts, increases in creatinine levels, increases in aminotransferases, and increases (16-22%) in LDL/HDL cholesterol levels
  4. Four deaths were noted among patients treated with tofacitinib compared with none in the methotrexate patients.

Related blog post: Source Article: Methotrexate Safety | gutsandgrowth