Category Archives: Pediatric Gastroenterology Intestinal Disorder

Limiting Cow’s Milk for EoE

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A small retrospective study suggests that eliminating cow’s milk, without other interventions, can be effective in the treatment of Eosinophilic Esophagitis (EoE) (JPGN 2012; 55: 711-16).

Out of 161 children with EoE, 17 patients were identified who excluded only cow’s milk from their diet.  Remission was noted in 65%.  Complete histologic remission (≤1 eosinophil/hpf) was noted in 7 patients (41%) and 4 (24%) had “significant remission” (defined as peak eosinophil count of 2-15/hpf).

This study, conducted in Chicago, took place between 2006-2011.  The majority of the patients treated at this institution are treated with dietary elimination: 61% with empiric elimination diet, 8% empiric elimination diet with topical steroids, and 7% with elemental diet.

The authors suggested that younger children may be more likely to benefit from this approach but cautioned against drawing firm conclusions due to the small ‘scope’ of this retrospective study.

 Related posts:

T-cell therapy for Crohn’s disease

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Data from the Crohn’s and Treg Cells Study (CATS1) are very preliminary but indicate that administration of antigen-specific T-regulatory cells (Tregs) to refractory Crohn’s disease (CD) patients could be effective (Gastroenterol 2012; 143: 1207-17).  Tregs are specialized subpopulations of T-cells.

In this study, the investigators, performed a 12-week open-label multicenter single injections study of 20 patients with refractory CD.  After withdrawing blood from patients, mononuclear cells were isolated and cultured.  Subsequently, T cells were cloned.  A specific subset with high IL-10/IL-13 production and low IL-4 production were selected.

Key findings:

  • 8 of 20 (40%) patients had a CDAI reponse at 5 and 8 weeks.  This was associated with a reduction in serum CRP and a trend of decreasing fecal calprotectin.
  • Remission was noted in 3 patients at week 5 and in 2 patients at week 8.
  • Overall, regardless of dose used, the safety profile was “in line” with severe active refractory CD.  Gastrointestinal adverse events were common.  7 patients had CD flares. One patient died due to suicide.

To understand this study more fully, an accompanying editorial is in the same issue (pages 1135-38).  A more complete discussion of the function of Treg cells is given, included their physiologic role of patrolling the gut lamina propia for antigens ‘derived from food and commensal flora.’  Circulating Treg cells may be deficient in IBD patients and thus contribute to the pathogenesis.

While injecting Treg cells may become a useful therapy, other ways of boosting Treg cells may be enhanced as an alternative.  Currently, granulocyte colony-stimulating factor (GCSF), anti-TNFα agents, and IL-2 all have the potential to enhance Treg cell function.  This supports the editorial’s conclusion that ‘Treg cells are rapidly moving from the bench to the bedside.’

Given the experimentation with stem cell therapy and bone marrow transplantation for CD, Treg cells show promise of a much more targeted effect on the immune system.

Additional references:

  • -Blood 2010; 116:6123-32.  Autologus stem cell transplantation in patients with refractory CD.
  • -Gut 2008; 57: 211-17.  Autologus stem cell transplantation for refractory CD.
  • -Gut 2010; 59: 1662-69.  Mesenchymal stromal cell treatment for luminal Crohn’s.

Green beans for short gut syndrome

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A recent article indicates that the addition of green beans may improve diarrhea and reduce dependence on parenteral nutrition (Adding Dietary Green Beans to Formula Resolves the Diarrhea …) (ICAN. DOI: 10.1177/1941406412469403). Thanks to Kipp Ellsworth for pointing out this reference on his twitter feed.

This small retrospective study of 18 infants examined the addition of green beans to the diet of infants with short bowel syndrome (SBS) (1 jar of stage 2 baby food green beans to every 8 ounces of 30 cal formula).  The average gestational age of the patients was 32 weeks (range 23-39 weeks) and the average birth weight was 1938 gram.  Nine patients had NEC, four had gastroschisis, two had Christmas tree defect, and three had other reasons for either SBS or intestinal failure.  The IF group (n=10) was defined as being dependent on parenteral nutrition to meet nutritional needs; the SBS group (n=8), who were more severely affected, was defined as the malabsorptive state that follows a massive resection.

Products that were used:

  • Gerber Natural Select: 3 gm of fiber per 4 ounce
  • Beach-Nut Homestyle: 2 gm of fiber per 4 ounce
  • HyVee Mother Choice: 2 gm of fiber per 4 ounce
  • These products average 32% soluble and 68% insoluble fiber

While the authors note that they use only amino-acid based formulas currently, at the time of the study, 61% were receiving Peptamen Junior.

It is not clear in the manuscript exactly at what age green beans are introduced. However, a previous case study suggested addition of green beans at ~4 months or >44 weeks postconception.  This prior case study indicated that adding stage 2 green beans changed the caloric density of 30 cal formula to 22 cal/ounce (Nutrition in Clinical Practice 2005; 20: 674-77).  In addition, this adds 2 gm/kg/day of fiber.

Results from current study:

  • 9 of 10 IF patients were able to discontinue parenteral nutrition
  • 2 of 8 SBS patients were able to discontinue parenteral nutrition
  • All infants had improvements in stool consistency, typically within 24 hours of dietary change.

While the authors acknowledge the limitations of the study, they hypothesize that the reason for improvement is due to the fiber content of green beans.   Fermentation of dietary fiber produces short chain fatty acids (SCFAs) which in turn have a trophic effect on the mucosa and enhance nutrient absorption.

Studies have shown that adults with IF or SBS have improved stool consistency with the addition of fiber.  However, the authors note that there have been no studies documenting the effectiveness of dietary fiber in the pediatric SBS/IF population.

Whether green beans would outperform other sources of fiber like pectin, guar gum, bananas or benefiber is not clear.

Additional references/links:

Feeling the urge and stopping the shame

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So many parents misinterpret withholding behavior in children.  Many indicate that their child is trying to go but cannot and others indicate that their child does not feel an urge to defecate.  Now more insight into this common issue has emerged (JPGN 2013; 56: 19-22).

The authors reviewed their experience with colonic manometry (n=410).  150 patients were identifed as having functional constipation.  Among this group, 56 patients volunteered that they had no urge to defecate.

Yet, during colonic manometry, when the first high-amplitude propagating colonic contraction (HAPC) occurred, this was associated with retentive posturing, grimacing or denial of sensation.  When the HAPC occurred, the examiner would explain that it was causing pain that would improve if the child defecated.  Ultimately, “every patient acknowledged an urge to defecate and successfully defecated.”

One other interesting part of this publication is the discussion of psychological aspects.  Do you remember Erikson’s stages (Erik Erikson – Wikipedia, the free encyclopedia)?  The authors note, “if toilet training is not achieved or the process involves negative experiences including being shamed into the process, shame and doubt will persist.  Shame, according to Erikson, is an infantile emotion and leads to secretive behavior.  Therefore, children who failed toilet learning may deny sensations of the urge to defecate…all the while having shame and embarrassment.”

These psychological issues are important in the propagation of constipation. The authors note that, even in children with rectal distention due to chronic constipation which could result in decreased sensation, studies have shown rectal compliance was not associated with treatment failure.  Therefore, constipation and soiling are not simply due to a mechanical issue of not knowing when to go.

Related posts:

Colic Microbiome

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A new study identifies a potential microbiome signature that is associated with colic (Pediatrics 2013; 131: e550-58). Thanks to Mike Hart for this reference.

With new technology, the microbiome’s role in many gastrointestinal conditions is being unraveled.  For colic, there has been concern about that an abnormal microbiome has been contributing to the pathophysiology.  On a personal level, I have had an interest in this subject for quite a while:

In this current study, the authors serially followed the microbiome infants in a prospective longitudinal project.  Nine stool specimens were obtained from each infant. Four were obtained in the first month at day of life 2, 7, 14, and 28 days.  Five were obtained at 3 to 5 months.  All specimens were stored at -20°C until analyzed by the “Human Intestinal Tract Chip (HITChip).” The HITChip microarray was considered satisfactory if 2 independent hybridizations had >95% correlation.  These microarrays “showed a dynamic range of >10,000-fold and >200 independent microarray readouts were used.”

Of 160 healthy term infants, the authors identified colic in 25% who averaged >180 minutes of crying per day over a four-day period.  Then, the authors selected the 12 infants who cried the most and compared them to the 12 infants who cried the least.

Results:

  • In the infants who were highly similar, the “infants with colic showed a significantly reduced microbiota diversity at 14 and 28 days of life.”  Proteobacteria, including Enterobacter aerogenes, Escherichia coli, and Klebsiella pneumoniae, were increased with more than a doubled abundance.  Bifidobacteria and lactobacilli were decreased in colicy infants.
  • At about 3-4 months of age, the colic group had a similar microbiome as the non-colicy group.
  • The authors speculate that proteobacteria might cause inflammation and may displace helpful bacteria.  Certain butyrate-producing bacteria like Butyrivibrio crossotus and Coprococcus estates were more commonly present in the non-colicy group.  The authors note that butyrate reduces the pain sensation in adults.

Bottom-line:

These results could explain why administration of probiotics (and possibly antibiotics) can result in a decrease in colic symptoms.

Related blog entries:

Additional references:

  • -Pediatrics 2010; 126: e526.  Double-blind randomized placebo-controlled trial of Lactobacillus reuteri.
  • -J Pediatr 2009; 155:823. Increased calprotectin in colicy infants. n=36. editorial pg 772.
  • -J Pediatr 2009; 154: 514-20. Colic and reflux. (Orenstein et al), & 475 (editorial -Putnam). PPIs (lansoprazole) do not help colicy Sx in infants c GERD. n=162. Increased resp infections in pts on PPIs. 44% response in Rx & control group.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Pediatrics 2005; 116: e709. Low-allergen maternal diet was helpful.
  • -Arch Pediatr Adol Med 2002; 1183 &1172. lack of sequelae on maternal mental health.
  • -Arch Pediatr Adol Med 2002; 156: 1123-1128. colic 24% of infants, breastfeeding did not help.
  • -Pediatrics 2002; 109: 797-805. carbohydrate malabsorption with breath testing in colicy infants, n=30. 2 hour fasting period.
  • -Arch Dis Child 2001; 84: 138-41. Lack of benefit (vs placebo) of chiropractic manipulation for colic, n=100. 86 completed study. 70% improved vs 60% in placebo.
  • -JPGN 2001; 33:110-111. Lack of assoc c GER
  • -Pediatrics 2000; 106: 1349. Use of hydrolysate decreased crying by 63mins/day
  • -Pediatrics 2001; 108; 878-882. No assoc between colic and markers of atopy/asthma/allergy.

Predictors of colectomy in pediatric UC

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A recent review of children in the Pediatric Inflammatory Bowel Disease Consortium (PediIBDC) examined risk factors for proctocolectomy in children with Ulcerative Colitis (UC) (JPGN 2012; 55: 534-40).  Two of the investigators (Stanley Cohen and Ben Gold) are colleagues of mine at GI Care for Kids.

In total, 406 children with UC were reviewed.  The average age at diagnosis was 10.6 years.  The average followup was 6.8 years.  57 (14%) underwent surgery with a median time to surgery of 3.8 years.  Overall risk factors for colectomy included the following:

  • Presenting with weight loss, HR 2.55
  • Presenting with hypoalbuminemia (<3.5 g/dL), HR 6.05
  • First-degree relative with UC, HR 1.81
  • Treatment with cyclosporine, HR 6.11
  • Treatment with tacrolimus, HR 3.66

While this data expands on the knowledge of these factors in children, the findings are not unexpected.  Low albumin levels and poor nutritional status have been identified in other studies as risk factors for UC relapse and for colectomy.

With regard to first-degree relatives, the findings imply that children with a first-degree relative are more likely to have a more severe form of UC.

The use of calcineurin inhibitors, cyclosporine and tacrolimus, are given only in the presence of severe disease.  Thus, while use of these agents is associated with an increased risk of colectomy, it is unlikely that this is a causal relationship.  Interestingly, the use of infliximab was not identified as a risk factor.  However, this retrospective study examined patients between 1999-2003.  Since this timeframe, there has been increased use of infliximab for refractory UC.

Going forward, it is likely that contemporary studies would incorporate PUCAI (pediatric UC activity index) measurements and would have the ability to enroll far greater numbers of patients from database consortiums.

Related blog posts:

Transfusion strategy in acute GI bleeding

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A recent study shows that holding off on blood transfusions can improve survival with severe acute upper gastrointestingal bleeidng (NEJM 2013; 368: 11-21).  This finding is not unexpected as this has been shown in observational studies.  In addition, in critical care patients without acute GI bleeding, a restrictive approach to transfusions has also been beneficial.

This study which enrolled 921 patients (>18 years) assigned 461 to a restrictive transfusion strategy (transfusion if <7 g/dL or at discretion of physician) and 460 to a “liberal” strategy (transfusion if <9 g/dL).

In additon to fewer transfusions, the restrictive group had improved survival:

  • 225 in the restrictive group did not require a blood transfusion compared with 65 in the liberal group
  • Survival at 6 weeks: 95% in the restrictive group compared with 91% in the liberal group.  Hazard ratio 0.55 (confidence interval 0.33 to 0.92) –a 45% reduction in the relative risk of 45-day mortality.
  • Recurrent bleeding occurred in 10% of the restrictive group compared with 16% of the liberal group.
  • The patients with cirrhosis (and Child-Pugh class A or B) were most likely to benefit from a restrictive approach with hazard ratio of 0.30.  Child-Pugh class C did not have a benefit from a restrictive approach with hazard ratio of 1.04.  With the liberal approach, there was a higher portal-pressure gradient within the first five days.

The reasons for bleeding in this study included peptic ulcers in about 50%, and varices in 24%.  The other causes included Mallory-Weiss tears, erosisve gastritis/esophagitis, and neoplasms.

Why does giving less blood result in better outcomes?

  1. Transfusion may impair hemostasis in several ways.  It may result in abnormalities in coagulation properties.  It may counteract splanchnic vasoconstrictive response.  And, in those with cirrhosis, it can increase portal pressure (even in the presence of somatostatin).  All of these mechanims may increase rebleeding.
  2. In addition, systemic effects from transfusion can include circulatory overload and pulmonary edema.

Also (unrelated to this posting), a thoughtful comment to a recent post on FDA regulations was posted by Ben Gold (Can the FDA prohibit free speech? | gutsandgrowth).

Related blog references:

Fecal transplant -now mainstream

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This blog has previously discussed fecal transplants (see below).

Now, in response to an article in the New England Journal of Medicine, this topic is discussed in the NY Times:

Fecal Treatment Gains Favor for Some Illnesses – NYTimes.com

http://www.nejm.org/doi/full/10.1056/NEJMoa1205037?query=featured_home

(method: duodenal infusion)

Related blog links:

Kawasaki disease –there’s an app for that!

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With the ubiquitous availability of smart phones, point-of-care technology becomes increasingly sophisticated.  Many are familiar with mobile drug information resources (eg. Lexicomp, Epocrates), but now information is increasingly disease-specific.  An example of this and the data supporting this are available in a recent publication with regards to diagnosing Kawasaki disease(KD) (J Pediatr 2013; 162: 183-88).

After simulating a model with a training cohort of 276 patients with KD and 243 febrile control (FC) patients, the authors validated the model with 136 patients with KD and 121 FCs.  Inclusion criteria for KD were based on the American Heart Association guidelines.

The scoring system which combined clinical findings and laboratory findings resulted in “a sensitive (>95% PPV) and specific (>95% NPV) diagnosis of ~60% of FCs and ~75% of patients with KD.”  In essence, the patients with high or low scores for KD were quite reliable.

To check out the web site:

http://translationalmedicine.stanford.edu/cgi-bin/KD/kd.pl

Potential limitation: The personnel involved in the study were very experienced in KD; thus, the model may be less effective when less skilled personnel obtain the clinical information.

While pediatric gastroenterologists do not frequently see KD patients, the bigger issue is developing point-of care tools. In our electronic health record (EHR), one point-of-care tool I developed was a smart phrase to assess hospitalized patient’s with colitis (see bottom of post in blue).  This smart phrase can be pulled up with three key strokes and helps me assess the severity of the patient’s colitis.

Another useful smartphrase in blue  (that was shared with me from Mike Hart), also retrieved with three key strokes,  is the following:

Here is a weblink on youtube for a video on changing Mic-Key buttons:

http://www.youtube.com/watch?v=Mn4ePSBiCTk

I often share this link with parents at the end of my “after visit summary” note.

These types of tools can improve recognition and treatment in a wide range of areas and are only limited by our imagination.

Pediatric UC Activity Index:

1. Abd pain

No pain —0 points, Pain can be ignored —5 points, Pain cannot be ignored—10 points

2. Rectal bleeding

None —0 points, Small amount & in <50% of stools — 10 points, small with most stools —20 Large amount —30 points

3. Stool consistency

Formed — 0 points, partially formed — 5 points, completely unformed —10 points.

4. #Stools/24hrs

0-2 —0 points, 3-5 —5 points, 6-8 — 10 points, > 8 15 points

5. Nocturnal Stools

No —0 points, Yes —10 points

6. Activity Level

No limitation —0 points, Occasional limitation —5 points, Severe limitations —10 points

 

Total Score: *** @TD@ 

 

Interpretation: 

Remission <10, Mild dz 10-30, Mod dz 31-64, Severe dz >65

 

References: 

1. Gastroenterology 2010; 138: 2282-2291.  PUCAI helps predict IV steroid failure in hospitalized pediatric colitis pts. n=128.  37 failed IV steroids (29%)

Score >45 (on day 3) indicates pts likely to fail IV steroids: Pos PPV 43%, Neg PPV 94%

Score >70 (on day 5) indicates need for alternate rx (+PPV100%) 

25/33 steroid failures responded to IFX.  Colectomy rate 9% initial, & 19% at 1 year.

2. Gastroeterology 2007; 133: 423-32.  Turner et al.

Related blog entry:

Cholestatic Kawasaki Disease | gutsandgrowth

Predicting long-term response with calprotectin levels

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This blog has been a fan of calprotectin levels (see related posts below) as both a screening test for inflammatory bowel disease and as a marker of disease activity.  Now more data is available indicating that calprotectin levels, much like endoscopic mucosal healing, after induction therapy correlates with long-term response (Inflamm Bowel Dis 2012; 18: 2011-17).

This retrospective study (2005-2010) examined 60 patients with IBD with elevated baseline calprotectin levels.  34 patients had Crohn’s disease (CD) and 26 had ulcerative colitis (UC).  42 patients received infliximab therapy and 18 patients received adalimumab.  After induction therapy, therapy was discontinued in primary non responders or continued as scheduled maintenance therapy for at least one year if not relapsing.

The average age at induction for CD patients was 30 and the corresponding age at diagnosis was 21.  For UC patients, the average age at induction was 29 and the corresponding age at diagnosis was 26.

Median calprotectin level at baseline was 810 μg/g (n=60).  After induction, the median value dropped to 97 μg/g (n=60) and at 1 year the value dropped to 27 μg/g (n=25).  The calprotectin level normalized in 31 patients after induction.  At 12 months, the sustained remission was present in 84% (26/31).  In contrast, only 38% (11/29) who had elevated levels after induction were in remission at 12 months.

Related blog entries: