Category Archives: Pediatric Gastroenterology Intestinal Disorder

Ustekinumab for Crohn’s Disease

Posted on by

Ustekinumab is emerging as an option for inflammatory bowel disease.  A study examining its effectiveness for TNF-refractory Crohn’s disease has been published (NEJM 2012; 367: 1519-28).

In this trial, members of CERTIFI (Crohn’s Evaluation of Response to Ustekinumab Anti-Interleukin-12/23 for Induction) from 153 centers in 12 countries assessed the efficacy of Ustekinumab in 526 adult patients.  The primary outcome was a clinical response (CDAI >100 point drop) at 6 weeks.

Ustekinumab (currently approved for plaque psoriasis) is a ‘fully human IgG1κ monoclonal antibody’ which blocks the activity of interleukin-12 (IL-12) and interleukin-23 (IL-23) by inhibiting receptors on T cells, natural killer cells, and antigen-presenting cells.  IL-12 and IL-23 have been implicated in the pathophysiology of Crohn’s disease.

This study of ustekinumab was a 36-week randomized, double-blind, placebo-controlled phase 2b trial.  The first 8 weeks were for induction.  After induction, based on response, patients were enrolled in a 28-week maintenance phase.  Initial dosing was 1, 3, or 6 mg/kg of intravenous ustekinumab or placebo.  Maintenance dose was 90 mg subcutaneously.

Patients were permitted to continue receiving stable doses of drugs.  However, entry requirements included a washout period for intravenous glucocorticoids (3 weeks), TNF antagonists (8 weeks), and natalizumab (12 months).

Results:

  • 36.6%, 34.1% and 39.7% of ustekinumab patients (1, 3, and 6 mg/kg respectively) responded at 6 weeks compared with 23.5% of placebo.  The difference was statistically significant for 6 mg/kg/dose.
  • Maintenance therapy (among responders) noted increased clinical remission with ustekinumab compared with placebo 41.7%  vs 27.4%.
  • Overall rates of infection were similar. Serious infections were noted in 6 patients receiving ustekinumab compared with 1 placebo-treated patient.  Infusion reactions were uncommon.
  • Patients who did not have a response to ustekinumab in the induction phase did not benefit from additional ustekinumab in the maintenance phase.

Overall, in this study, patients dosed at 6 mg/kg during induction were more likely to have a response but not more likely to have a remission.  Since all patients in this study had failed at least one TNF antagonist and 50% had failed at least two, the benefit of ustekinumab in other Crohn’s disease patients remains undefined.

Related blog entries:

CHOOSE TNF TRIAL | gutsandgrowth

Vedolizumab -another new IBD treatment | gutsandgrowth

Adding Methotrexate to anti-TNF therapy | gutsandgrowth

Microbial transfer for metabolic syndrome?

Posted on by

Animal models have demonstrated an association between microbiota composition and obesity.  Now, a study shows that the transfer of intestinal microbiota from lean human donors to individuals with metabolic syndrome can improve insulin sensitivity (Gastroenterology 2012; 143: 913-16).

It is known that the small intestine has sensing mechanisms to improve insulin sensitivity via neuronal circuits and changes in microbe composition may be one of the stimuli for this mechanism.  Given the association of altered microbiota with obesity, the investigators divided 18 patients with metabolic syndrome to receive either an allogenic infusion (n=9) of gut microbiota or an autologus infusion (n=9) of gut microbiota.

All subjects underwent small bowel biopsies and then subsequently had lavage through a duodenal tube.  In the allogenic group, the infusate was derived from lean male donors (BMI <23 kg/m-squared).  Insulin sensitivity was measured before and 6 weeks after infusions.

Results:

  • Fecal microbiota of obese subjects was characterized by lower microbial diversity and higher amounts of certain microbes (eg. Bacteroidetes).
  • Peripheral insulin sensitivity improved after allogenic infusion with a median of 26.2 μmol/kg/min prior to 45.3 μmol/kg/min at the six-week measurement.  It was unchanged in those with the autologous infusion as noted in Figure 1.
  • Gut microbial diversity increased significantly after allogenic infusion 178 ± 62 –>234 ± 40 species.  It was essentially unchanged in the autologous group (from 184 ± 71 to 211 ± 50).  Heat maps (Figure 2) help illustrate the microbial changes in the subjects.
  • The authors conclude that butyrate derived from many of the increased bacterial group probably has a regulatory role in improving insulin sensitivity.  Butyrate can prevent translocation of endotoxic compounds derived from gut microbiota which can promote insulin resistance.

Perhaps in a few years, besides limiting the consumption of sugary beverages in places like NYC, beverages with “lean” microbes and or “lean” probiotics may become important.

Do we need clinical scores in pediatric pancreatitis?

Posted on by

A retrospective study (2003-2007) confirms the limited utility of severity scores in pediatric pancreatitis (JPGN 2012: 55: 266-67). The authors collected data from 48 children; 13 were considered to have severe acute pancreatitis (AP).

Three clinical scores, Ranson, Glasgow modified, and DeBanto, were compared; in addition, the Balthazar computed tomography (BCT) severity index was examined.  Based on their cohort, the clinical scoring systems had a specificity of about 85% but a poor sensitivity of about 55% (53-62%).  The BCT had a sensitivity of 80% and a specificity of 86%. Though, to limit radiation exposure, ultrasonography is preferred over routine use of CT scanning for most pediatric patients.

These data indicate that it is not necessary to remember Ranson’s criteria (or to download a app for that).

More “Survivin” in Crohn’s disease

Posted on by

Survivin is a member of the inhibitors of apoptosis family.  It helps regulate cell division and prevents cell death.  (Gastroenterology 2012; 143: 1017-26).  While survivin has been shown to be important in cancer, it appears to be important in inflammatory and autoimmune disorders.

In the referenced study, lamina propria T cells (LPT) were isolated from mucosal samples of patients with Crohn’s disease (CD), ulcerative colitis (UC), and controls.  Expression of survivin was assessed by immunohistochemistry, confocal microscopy, and immunoblotting.

LPTs from patients with Crohn’s disease had increased survivin levels; this was not seen in control patients or UC patients.  Furthermore, the investigators showed that the survivin (bound to heat shock protein) was resistant to proteasome degradation.

Implications of this study: 

Survivin may have crucial consequences for CD and other inflammatory/autoimmune diseases; cell proliferation and apoptosis alteration may be important in the pathogenesis of  in these disorders.

PEG vs. Fiber for constipation

Posted on by

Which is better for childhood constipation, polyethylene glycol 3350 (PEG) or fiber? A recent study weighs in (J Pediatr 2012; 161: 710-15).

This randomized, prospective, open-label study compared PEG (with electrolytes) to a fiber supplement (acacia fiber, psyllium fiber, and fructose [AFPFF]) in 100 children with chronic functional constipation (Rome III criteria).  Mean age was 6.5 years.  Study design allowed for dosage adjustment.  Initial PEG dosing was 0.5 g/kg but could be increased to 1 g/kg. AFPFF was dosed at 16.8 g daily but could be increased to 22.4 g.  Primary outcome was ≥3 bowel movements per week and improved stool consistency (≥2 on Bristol stool scale).

Key findings:

  • Compliance was better with PEG than AFPFF: 96% for 72%.
  • After 8 weeks, improvement noted in 83% of PEG patients compared to 78% of AFPFF (P=0.788).  At this time point, PEG were having ~5.8 stools/week vs. 5.6 for AFPFF.  Mean Bristol scores were 3.7 and 3.5 respectively.
  • Conclusion: similar efficacy but PEG had better acceptance.  No mention of relative costs of these agents is noted.

Additional references:

Diagnosis and management of idiopathic childhood constipation – BMJ  NICE (Nat’L institute for Health and Clinical Excellence) recommendations 2010

Also, a recent previous post (ACE report -10 year effectiveness | gutsandgrowth) has links to multiple related blog entries.

Microbiome in pediatric ulcerative colitis

Posted on by

Alterations in the gastrointestinal tract microbiome may play an important role in many digestive conditions.  A recent article examines microbiome alterations in children with severe ulcerative colitis (UC) (Inflamm Bowel Dis 2012; 18: 1799-1808).

Stool samples from 26 healthy children and 27 children with severe UC were prospectively studied.  After DNA extraction, PCR amplification and microarray hybirdization were performed and analyzed.   None of the patients in the study had received antibiotics or probiotics in the preceding month.

Key findings:

  • There were substantial reductions in “richness,” diversity, and evenness of the gut microbiome in UC patients.  (Richness is a term used to reflect the number of detected phylospecies.)
  • There was a decrease in signal in almost all  phylospecies.
  • The number of phylospecies was reduced in UC (266 ± 69) vs controls (758 ± 3)
  • Steroid responders had even fewer phylospecies compared with responders (142 ± 49  vs. 338 ± 62)

It is not surprising that the stools from these children are much different.  The issues of causation and whether a snapshot of the microbiome diversity will have clinical relevance is not clear.  It is possible that antimicrobials may make an individual more susceptible to inflammatory bowel disease by altering the individual’s microbiome.

Related blog entries:

Eat your veggies…if you don’t want to get sick | gutsandgrowth

Why are we seeing so many more cases | gutsandgrowth

ACE report -10 year effectiveness

Posted on by

More data is now available on the use of antegrade continence enema (ACE) for difficult-to-treat defecation disorders (J Pediatr 2012; 161: 700-4).

This study reports the 10-year (retrospective) experience of a single center.  In total there were 99 patients, median age 8 years.  Mean time for followup was 46 months.  Most procedures were undertaken by interventional radiology with temporary  8.5 Fr Dawson-Mueller catheter which was changed to a Chait Trapdoor catheter after six weeks.  All patients received triple antibiotics for 48 hours and then oral metronidazole for 7 days.  While ACE were not started for 10-14 days, the tube was irrigated with 10 mL of normal saline BID after placement.

Key findings:

  • 71% became symptom-free, and an additional 20% improved significantly
  • Patient population: 35 with functional constipation, 29 with spinal abnormalities, 8 with cerebral palsy, 8 with Hirschsprung’s, 7 with imperforate anus, 7 with combined imperforate anus/tethered cord, and 5 with other causes
  • Irrigations with a stimulant seemed to be more effective.  Specific stimulants included bisacodyl (5 mg if patient <10 years and 7.5 mg if >10 years) and glycerine (median dose 37.5 mL).
  • In the 7 patients without improvement, the stoma was closed after a median time of 7 months & 5 ultimately underwent colostomy.
  • Risk factors for poor outcome: younger age, shorter duration of symptoms, Hirschsprung’s disease, cerebral palsy, previous abdominal surgery, and abnormal colonic manometry (Previous studies have not shown that preop manometry helpful in predicting outcome of ACE).
  • 13% of patients were able to discontinue ACE without recurrence of symptoms
  • Major complications occurred in 12 patients.  12 patients had infections, 4 had abscess, and 3 had peritonitis.  Minor complications were commonplace including leakage in 21 and granulation tissue in 41 patients.

I think this report does provide a balanced view of cecostomy/appendicostomy placement; this will be helpful in counseling families.  While the majority of children will be able to irrigate their colon and thus minimize their intractable constipation, many will have issues with the tube site and particularly early on there is a risk of serious infections.

Related blog entries:

Clues about constipation and more than 2.5 million views …

Stimulants for constipation | gutsandgrowth

It’s worth the cost | gutsandgrowth

thyroid | gutsandgrowth

Additional references:

  • Percutaneous Endoscopic Colostomy (PEC) – YouTube (LEFT-SIDED PROCEDURE)

  • -J Pediatr Surg 2010; 45: 213-9.  ACE highly effective for intractable constipation
  • -JPGN 2011;52: 574.  n=117. 69% success with antegrade enemas.
  • -JPS 2002; 37: 348-51.  sigmoid irrigation.
  • -Lancet 1990; 336: 1217. Malone’s initial description.

Once daily Mesalamine

Posted on by

Based on the literature, it is not clear that there is any need to give melamine more than once a day; this is often in contrast to labeling for many of these products:

  1. Inflamm Bowel Dis 2012; 18: 1785-94 
  2. Inflamm Bowel Dis 2012; 18: 1885-93

The 1st study identified 11 relevant randomized studies, after excluding 6870 that were considered irrelevant. Five of these studies were single blind and one was open-label; the remainder were double-blind randomized trials. In total, these studies examined 4070 patients.

Mesalamine products studied: Mesalazine (Salofalk), MMX mesalamine, Asacol, and Pentasa

Summary of findings:

  • Failure to induce clinical remission: relative risk (RR) with once daily 0.95; absolute risk 421 per 1000 in once daily group
  • Failure to induce clinical improvement: RR 0.87; absolute risk 398 per 1000
  • Failure to maintain clinical remission at 12 months: RR 0.92; absolute risk 286 per 1000
  • Failure to adhere to study medication regimen: RR 1.21; absolute risk 128 per 1000

Thus, this meta-analysis indicates that once daily dosing is as effective as conventional dosing for both induction and maintenance, at least with the formulations that were tested. Also, in this meta-analysis, adherence was not improved with once daily therapy, though some previous studies have indicated that once daily therapy may be helpful particularly in the first few months of treatment.

The 2nd study examined 213 patients for maintenance of UC remission; patients were randomized to receive either Asacol 2.4 g once a day (QD) or 800 mg three times a day (TID). Patients were treated at 32 UK centers and had an average age of 50 years. Relapse rates were 31% for QD therapy and 45% for TID over 1 year.  This study showed that QD was noninferior to TID and possibly superior, perhaps due to improved adherence.

Perhaps it is time to give all mesalamine products once a day.

Outcomes with STEP procedure

Posted on by

While the serial transverse enteroplasty (STEP) procedure has been considered a major advance in the management of short bowel syndrome (SBS), long-term data are in short supply.  5-year outcomes from Toronto with regard to 12 patients offers some insight into the effectiveness of this operation (J Pediatr Surg 2012; 47: 931-37).

The 12 patients selected for this study received STEP prior to January 2005.  The other 19 STEP patients at this institution were not included due to lack of long-term followup. Among the 12 patients, 6 had intestinal atresia, 3 had NEC, 1 had gastroschisis, 1 had volvulus, and 1 had Hirschsprung disease.

Key results:

  • 7 patients weaned off parenteral nutrition successfully –one took 4 years; one patient continued on parenteral nutrition.
  • 2 patients died of liver failure, 2 patients received liver-intestinal transplant.
  • STEP increased small bowel length from a median of 110 cm to 128 cm.  The dilated portion that received STEP changed from a median length of 31 cm to a median of 57 cm; this resulted in a median bowel caliber change from 6 cm to 2 cm.  The overall effect was an overall increase in small bowel length of 40%.
  • Biochemical markers improved.  For example, citrulline increased from 18 μmol/L pre-STEP to 33 μmol/L at 12 months, and 48 μmol/L at 5 years post-STEP.  Fecal fat malabsorption (based on 72 hr collections) improved from >40% to ~20% 6 months after STEP.
  • Indications for STEP: bacterial overgrowth (n=7), intestinal failure associated liver disease (IFALD) (n=5).
  • Complications: suture line bleeding due to ulcerations in one patient, 2 patients had leakage at suture line in immediate post-op period.  The latter 2 cases were ascribed to limited experience with technique; the surgeons now use a 2.5 mm staple instead of a 3.5 mm.

Take home points:

  1. Authors comment: “our approach is to only consider patients who plateau in their parenteral nutrition weaning or develop complications such as PN cholestasis…patients who continue to show intestinal adaptation are not offered surgery despite the presence of bowel dilatation”
  2. “It takes up to an average of 1 to 2 years to see the improvement in intestinal function after a STEP.”  While the authors may be correct about this timeframe, in their figure 3, two came off PN at one month post-STEP, four achieved this goal 6 months after STEP and another 12 months following STEP.
  3. Why does STEP work? Either improved intestinal function due to increased absorptive surface or due to healing of existing mucosa; the latter may occur with resolution of dilated,  inflamed bowel associated with bacterial overgrowth.

Related blog entries:

Four advances for intestinal failure | gutsandgrowth

IFfy outcome | gutsandgrowth

Additional STEP references:

  • -JPGN 2007; 45: 174, 257.
  • -J Pediatr Surg 2003; 38: 425-429. Initial description of STEP procedure from Kim HB et al.
  • -Clin Gastro & Hep 2006; 4: 1237. STEP in 4 patients helped to decrease or eliminate TPN requirements.
  • Images for step procedure

Median Arcuate Ligament Syndrome

Posted on by

PEDIATRIC SURGERY UPDATE: VOL 39 NO 03 SEPTEMBER 2012 has a concise review of Median Arcuate Ligament Syndrome (MALS) along with some references -listed with other references below (thanks to Ben Gold for this reference).  MALS occurs when a fibrous portion of the diaphragmatic crura crosses the celiac artery and compression occurs. This disorder is described as a diagnosis of exclusion.  Symptoms may include weight loss, nausea, abdominal pain, vomiting, and diarrhea.  Imaging modalities including CT angiography, MR angiography or arteriography can increase the suspicion for this disorder.

While not alluded to in this reference, one of the problems is knowing whether MALS is a spurious finding.  That is, in young individuals there is typically a robust blood supply to the intestine and it is not clear whether compression of the celiac trunk is responsible for specific symptoms as there is a compensatory blood supply.

Fortunately this disorder is very rare (or at the very least rarely recognized).  One of the most experienced vascular surgeons relayed his experience over more than three decades.  He stated that he had operated on four cases of suspected MALS –two improved with surgery.  A better batting average than Chipper Jones! –but a lot fewer at bats.

References:

  • –Median arcuate ligament syndrome – Wikipedia, the free encyclopedia “It is estimated that in 10-24% of normal, asymptomatic individuals the median arcuate ligament crosses in front of (anterior to) the celiac artery, causing some degree of compression.”
  • – Median Arcuate Ligament Syndrome – YouTube
  • -Alehan D, Dogan OF: Pediatric surgical image. A rare case: celiac
    artery compression syndrome in an asymptomatic child.  J Pediatr Surg.
    39(4):645-7, 2004
  • – Gander S, Mulder DJ, Jones S, Ricketts JD, Soboleski DA, Justinich CJ:
    Recurrent abdominal pain and weight loss in an adolescent: celiac artery
    compression syndrome. Can J Gastroenterol. 24(2):91-3, 2010
  • – Said SM, Zarroug AE, Gloviczki P, Shields RC: Pediatric median arcuate
    ligament syndrome: first report of familial pattern and  transperitoneal
    laparoscopic release. J Pediatr Surg. 45(12):e17-20, 2010
  • – Aschenbach R, Basche S, Vogl TJ: Compression of the celiac trunk caused
    by median arcuate ligament in children and adolescent subjects: evaluation
    with contrast-enhanced MR angiography and comparison with Doppler US
    evaluation.  J Vasc Interv Radiol. 22(4):556-61, 2011
  • – Ozel A, Toksoy G, Ozdogan O, et al: Ultrasonographic diagnosis of
    median arcuate ligament syndrome: a report of two cases. Medical
    Ultrasonography 14(2): 154-157, 2012
  • – Wani S, Wakde V, Patel R, et al: Laparoscopic release of median arcuate
    ligament. J Minim Access Surg 8(1): 16-18, 2012
  • – “Median arcuate ligament syndrome”.Curr Treat Options Cardiovasc Med 2008 10 (2):
  • -“Median arcuate ligament syndrome: evaluation with CT angiography”. Radiographics 2005; 25 (5): 1177–82.