Category Archives: Pediatric Gastroenterology Intestinal Disorder

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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Safety Signal for Anti-TNFs

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In a large population of inflammatory bowel disease patients, anti-tumor necrosis factor medications (anti-TNFs) did not increase the risk of cancer in a recent study from Denmark.  This link provides a summary of the study (JAMA 2014 June 17 [doi:10.1001/jama.2014.5613]) in GI & Hepatology News: Anti-TNFs -Safety Signal

Here’s an excerpt:

This study “assessed the risks of any cancer and 11 individual cancers, including malignant melanoma, in 56,146 IBD patients aged 15 and older…during 1999-2012, of whom 4,553 took TNF-alpha antagonists.  Median follow-up was 9.3 years…A total of 6.7% of the patients who never took TNF-alpha antagonists developed cancer during follow-up compared with 1.8% of patients who took the drugs…

Stratifying for cancer risk according to years since first exposure, no specific time-dependent pattern was observed in our study…an increased risk in the long term cannot be excluded.”

In another systemic review study (Clinical Gastroenterology and Hepatology Volume 12, Issue 9, Pages 1443–1451, September 2014) focused on pediatric IBD patients (n=5528), the authors found that “Two patients developed lymphoma (2.1/10,000 PYF). This value was … lower than the population of pediatric patients receiving thiopurine monotherapy (4.5/10,000 PYF; SIR, 0.47; 95% CI, 0.03–6.44)”…”the risk of lymphoma was no greater among children with IBD who received anti-TNF therapy than those treated with other IBD therapies or adults treated with anti-TNF agents. The rate of serious infection was significantly lower among pediatric patients with IBD treated with anti-TNF agents than those treated with steroids, or adults with IBD who received anti-TNF therapy.”  Here’s the link: anti-TNF therapy with lower lymphoma risk than thiopurines in pediatrics

How Proton Pump Inhibitors Can Cause Infections

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In yesterday’s blog, the editorial on “Acid-reducing agents in infants and children: friend or foe?” also commented on an additional study (JAMA Pediatr. 2014. doi: 10.1001/jamapediatrics.2014.696) which addresses the issue of how proton pump inhibitors (PPIs) may contribute to an increased risk of infections.  It is well-known that use of PPIs (and to a lesser extent histamine-2 receptor antagonists) contribute to a significant increased risk of community-acquired pneumonias and gastrointestinal infections (probably including necrotizing enterocolitis in infants).

In this study, (from the editorial) “acid suppression was associated with a positive gastric culture (P =.003) and increased median concentration of gastric bacteria (P<.001). Full-column nonacid reflux was associated with higher concentrations of bacteria in the lung.”

In this era of pioneering microbiome research, it is not surprising that chronic changes in gastric acid production could cause these results.  This is something to consider when calculating risks and benefits, particularly in situations where the benefits are quite minimal.

Here’s the abstract:

Importance  The use of acid suppression has been associated with an increased risk of upper and lower respiratory tract infections in the outpatient setting but the mechanism behind this increased risk is unknown. We hypothesize that this infection risk results from gastric bacterial overgrowth with subsequent seeding of the lungs.

Objectives  To determine if acid-suppression use results in gastric bacterial overgrowth, if there are changes in lung microflora associated with the use of acid suppression, and if changes in lung microflora are related to full-column nonacid gastroesophageal reflux.

Design, Setting, and Participants  A 5-year prospective cohort study at a tertiary care center where children ages 1 to 18 years were undergoing bronchoscopy and endoscopy for the evaluation of chronic cough. Acid-suppression use was assessed through questionnaires with confirmation using an electronic medical record review.

Main Outcomes and Measures  Our primary outcome was to compare differences in concentration and prevalence of gastric and lung bacteria between patients who were and were not receiving acid-suppression therapy. We compared medians using the Wilcoxon signed rank test and determined prevalence ratios using asymptotic standard errors and 95% confidence intervals. We determined correlations between continuous variables using Pearson correlation coefficients and compared categorical variables using the Fisher exact test.

Results  Forty-six percent of patients taking acid-suppression medication had gastric bacterial growth compared with 18% of untreated patients (P = .003). Staphylococcus (prevalence ratio, 12.75 [95% CI, 1.72-94.36]), Streptococcus (prevalence ratio, 6.91 [95% CI, 1.64-29.02]), Veillonella (prevalence ratio, 9.56 [95% CI, 1.26-72.67]), Dermabacter (prevalence ratio, 4.78 [95% CI, 1.09-21.02]), and Rothia (prevalence ratio, 6.38 [95% CI, 1.50-27.02]) were found more commonly in the gastric fluid of treated patients. The median bacterial concentration was higher in treated patients than in untreated patients (P = .001). There was no difference in the prevalence (P > .23) of different bacterial genera or the median concentration of total bacteria (P = .85) in the lungs between treated and untreated patients. There were significant positive correlations between proximal nonacid reflux burden and lung concentrations of Bacillus (r = 0.47, P = .005), Dermabacter (r = 0.37, P = .008), Lactobacillus (r = 0.45, P = .001), Peptostreptococcus (r = 0.37,P = .008), and Capnocytophagia (r = 0.37, P = .008).

Conclusions and Relevance  Acid-suppression use results in gastric bacterial overgrowth of genera including Staphylococcus and Streptococcus. Full-column nonacid reflux is associated with greater concentrations of bacteria in the lung. Additional studies are needed to determine if acid suppression–related microflora changes predict clinical infection risk; these results suggest that acid suppression use may need to be limited in patients at risk for infections.

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GERD Treatment in Infants: “Friend or Foe”

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From a recent JAMA Peds editorial: (JAMA Pediatr. Published online August 18, 2014. doi:10.1001/jamapediatrics.2014.1263)

An excerpt:

Gastroesophageal reflux disease (GERD) is common in infants and children and has been estimated to affect as much as 3.3% of the pediatric population.1 Despite this, we still struggle with the management of GERD. With a growing body of literature that illustrates a lack of efficacy and alarming adverse effects, there is increasing reason to limit the empirical use of acid suppression therapy in children.

Other points highlighted in this editorial:

  • 36% of pediatricians prescribe PPIs for infants with uncomplicated regurgitation -“despite evidence and recommendations against this approach.”
  • 39% of pediatricians prescribed proton pump inhibitors (PPIs) for infants with unexplained crying
  • Conditions predisposing a child for severe GERD include those with neurological impairment, repaired esophageal atresia, cystic fibrosis, hiatal hernia, repaired achalasia, and lung transplantation.
  • In the related article ((JAMA Pediatr. doi: 10.10001/jamapediatrics.2014.1273), the authors reviewed 8 studies of histamine-2 receptor antagonists (H2RAs) and noted no improvement in overall symptoms infants.  In older age groups, H2RAs were more effective than placebo in symptom reduction, and histological healing.

Take-home message: “It is becoming clearer that in many circumstances, prescribing acid-reducing medication to infants is doing no good and increasing the risk of harm.”

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“Bacterial Penetration Cycle Hypothesis”

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Initially, this blog was titled: “Even More Work for Our IBD Nutritionists?”  If you get to the bottom of this post, you will know why.

A provocative study (Inflamm Bowel Dis 2014; 20: 1353-60) describes the use of partial enteral nutrition (PEN) as effective for induction of remission in children and young adults with Crohn’s disease (CD).  I’m a little wary commenting on this study as many individuals may take a glimmer of information and subject themselves to empiric trials.  In fact, a recent case report (N Engl J Med 2014; 371:668-675) described an adult who without medical advice used fecal transplant therapy (obtained from spouse and infant) to self-treat his ulcerative colitis.  In the case report, this patient ultimately was diagnosed with a secondary cytomegalovirus (CMV) infection and the fecal transplant was not effective.

With regard to the PEN study, the authors treated 47 patients (34 children) with up to 50% of their diet as a polymeric formula (Modulen or Pediasure) along with dietary counseling/changes.  The authors note that CD “may arise from a sequence of events involving changes in the microbiome, intestinal permeability leading to bacterial adherence or penetration of the epithelium, and subsequent stimulation of the adaptive immune response leading to tissue damage.  We have termed this sequence the Bacterial Penetration Cycle Hypothesis.”  Given the compelling improvements noted with exclusive enteral nutrition (EEN), the authors sought to modify the diet after an initial clinical response in two patients who could not adhere to EEN.

Design: Strict diet for 6 weeks with 50% of calories from formula, then less restricted diet for next 6 weeks (25% of calories from formula).  Also, diet required exclusion of gluten, dairy, animal fat, processed meats, products containing emulsifiers, candies, chocolates, gum, packaged snacks, sauces, and canned goods.  A more extensive listing of the foods is given in the appendix (page 1360).  The authors measured the clinical response with PCDAI, Harvey Bradshaw index, and bloodwork (eg. CRP, ESR, albumin, and hemoglobin).

Key finding:

  • 33 (70.2%) achieved a remission on this PEN diet; 78.7% (n=37) had a clinical response.
  • Normalization of CRP occurred in 21 of 30 patients (70%) of those with a clinical remission.

Take home message: A PEN diet needs more study.  I would not advise someone to radically change their diet without the instruction of a qualified nutritionist, unless the individual wants to be another case report of something gone awry.

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Hepatology Update -Summer 2014

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Preventing Perinatal Transmission of Hepatitis B Virus (HBV): Hepatology 2014; 60: 468-76.  This nonrandomized study, conducted between 2009-2011 with approximately 700 patients, showed that the rate of perinatal transmission of can be brought down almost to zero by instituting therapy with either telbivudine or lamivudine in the third trimester of pregnancy.  The accompanying editorial (pgs 448-51) indicates that either telbivudine or tenofovir (both pregnancy class B agents with regard to teratogenicity) are preferred agents due to higher barrier to resistance. And, the article suggests starting as early as week 28 (especially if high viral HBV DNA load) and no later than 32 weeks gestation. Other recommendations from editorial include stopping antiviral after delivery in women who intend to breastfeed.

More on coffee: Hepatology 2014; 60: 661-69.  Coffee but not tea conferred protection from cirrhosis mortality.  “Compared to non-daily coffee drinkers, those who drank two or more cups per day had a 66% reduction in mortality risk.”  This study also had an accompanying editorial (pg 464-67) which reviews the biologic plausibility and potential mechanisms.

NASH pathology: Hepatology 2014; 60: 565-75.  The study describes a more precise way to categorize the diagnosis of nonalcoholic steatohepatitis (NASH) using the European Fatty Liver Inhibition of Progression (FLIP) pathology consortium proposal.  The diagnosis of NASH requires the presence of ballooning and lobular inflammation in addition to steatosis.  Using the FLIP approach, diagnosis concordance increased significantly.

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For Pediatric GI MDs: Imaging and Anecdote in Cockayne Syndrome

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A brief article (J Pediatr 2014; 165: 416) discusses “susceptibility-weighted imaging” (SWI) for calcification in Cockayne syndrome.

SWI is a gradient-echo MRI sequence with a high sensitivity for blood, blood products, nonheme iron, and calcifications.

The reason why I highlighted this reference relates to a personal experience.  Several years ago I had a patient (about 8 years old at the time) who had mild GI symptoms along with very poor growth.  He had some mild neurologic features but extensive testing by several neurologists and a few well-qualified geneticists did not yield an answer.  Due to my concerns about his poor growth, I convinced the family to have their son admitted to our hospital before considering another trip out-of-town for further testing. As part of his evaluation, I reordered an MRI of his brain.  One of our radiologists (who is brilliant) called me up asking for clinical information and stated specifically that she was concerned about Cockayne syndrome.  After she mentioned the diagnosis, I questioned the family regarding some more specific features of Cockayne (e.g. photosensitivity).  Subsequently, genetic testing proved this child had Cockayne syndrome.

Cockayne syndrome is a rare autosomal recessive disorder that belongs to the family of damaged DNA repair disorders.  Besides photosensitivity and cachectic dwarfism, other features include neurosensory hearing loss, and progressive pigmentary retinopathy.  The physical features are quite characteristic –if you have seen a previous case!  The disease is rare enough that many experienced geneticists may not have seen a case.

Take-home message from this article: Careful MRI study of the brain, potentially with SWI, can help pinpoint the diagnosis of Cockayne syndrome.

On an unrelated matter, I wanted to thank Janet R for her note and let her know that she will be missed.

How Accurate is Serology at Predicting Mucosal Healing in Pediatric Celiac Disease?

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A recent study (Am J Gastroenterol doi: 10.1038/ajg.2014.200) shows that in children, unlike adults, that normalization of celiac disease (CD) serology correlates well with mucosal healing.

In this study, 150 children with biopsy-proven CD were prospectively evaluated with duodenal biopsies, tissue transglutaminase (tTG) IgA serology, and deamidated gliadin peptide (DPG) IgG serology.  After maintaining a gluten-free diet (GFD) for at least 1 year, participants underwent followup evaluation.

  • Of the 97 with normalization of their serology, 91 had normal biopsies (Marsh 0) and 6 had slight abnormalities (Marsh 1).
  • Of the 27 with positive serology, only 6 had Marsh 3 changes.
  • Overall, 124 (82.7%) had normalization of duodenal mucosal biopsies irregardless of serology.

Higher rates of mucosal healing are possible with longer duration of GFD.

On the other hand, a recent retrospective study (JPGN 2014; 59: 229-31) notes that among 40 children who underwent followup endoscopic evaluation (>4 months after GFD, median 24 months), most of whom were symptomatic, only 25 had complete healing. Though among those with adherence to a GFD, only five had persistent villous atrophy (Marsh 3 lesion) . Serological correlation was not provided.

Take-home message: Followup biopsies are not needed in children with normalization of their serology (tTG IgA and DGP IgG).  That is, serology correlates well with mucosal healing in children with celiac disease on a GFD >12 months. However, it is certainly reasonable to consider followup endoscopy in those who are symptomatic, especially if serology is abnormal.
In a related matter, the new requirements regarding gluten-free labeling have been implemented -here’s a link from the LA Times: Celiac Regulations or First federal gluten–free regulation takes effect

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Nutrient Deficiencies with Celiac Disease

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A recent study (JPGN 2014; 59: 225-28) examined fat-soluble vitamin deficiencies in pediatric patients with newly diagonosed Celiac disease (CD).

Of the 83 patients analyzed between 1995-2012 at the Mayo clinic, the key findings:

  • No patients had vitamin A deficiency
  • Two patients had vitamin E deficiency.  Both of these patients had complete villous atrophy along with a malabsorptive presentation.
  • Nine patients had mild-to-moderate vitamin D deficiency (less than the reported frequency in the general pediatric population)
  • All of these vitamin deficiencies corrected with gluten-free diet and vitamin supplements.

A limitation of the study was a selection bias as not all children underwent vitamin level measurements.

Take-home message (from authors): “fat-soluble deficiencies are uncommon in children with a new diagnosis of CD.  Routine measuring of fat-soluble vitamin levels may not be necessary.”

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One More Way to Prevent CVL Infections

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While a recent study (JPGN 2014; 59: 177-81) discusses the results of several strategies for limiting CVL infections, I found one approach in particular of interest.

This single center study (2009-2013, n=48 children) from Birmingham, UK examined a multidisciplinary enhanced care pathway regarding CVL care.  Implementation of this pathway lowered the risk of all-cause line infections from 1.98 per 1000 parenteral nutrition days to 0.45.  The pathway included training care providers, careful discharge planning, having those with skin conditions see dermatologists, and monitoring compliance.

One important observation was that methicillin-sensitive Staphylococcus aureus (MSSA) infections were often preceded by local signs of infection for a short period prior to systemic infection.  “We devised a pathway for exit site infections in which a swab is taken and empiric topical mupirocin commenced immediately. A decision on any further management is made after 24 to 48 hours.”

Take-home message: Implementing a CVL care pathway lowers CVL infections.  Implementing topical therapy at the first signs of a localized infection can be an important part of this effort.

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