Category Archives: Pediatric Gastroenterology Intestinal Disorder

SEED Journal Club: FPIES

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The main topic at this month’s SEED (SouthEast Eosinophilic Disease) Center Journal club was Food Protein-Induced Enterocolitis Syndrome (FPIES) with two featured articles:

  • J Allergy Clin Immunol In Practice 2013; 1: 317-22. Review
  • J Allergy Clin Immunol In Practice 2013; 1: 343-9. Original Study

The review covers the key issues including presentation, diagnosis, differential diagnosis, outcome and management. Some of the key points:

  • FPIES is characterized by repetitive emesis (often to the point of dehydration and lethargy) and sometimes diarrhea.  It typically starts within the first 3-6 months of life.
  • Trigger foods are most commonly milk, then soy, then grains (rice cereal). FPIES in exclusively breastfed babies is extremely rare.
  • FPIES is a non-IgE mediated reaction; thus testing with skin prick tests or serum for food-specific IgE has poor utility.
  • Differential diagnosis (Table E4): gastroenteritis/food poisoning, sepsis, anaphylaxis, inborn errors of metabolism, intussception, Hirschsprung’s, necrotizing enterocolitis, and proctocolitis
  • Variable time to resolution  (Table E6): Cow’s milk resolution up to 60% resolution by 10 months, though some studies report 60% resolution at 3 years.  Soy resolution as much as 90% by 10 months of age (less in other studies).  Solids -resolution in 67% by 3 years.
  • Management: Avoid trigger foods. If supplementing breastmilk, consider hydrolyzed (or amino acid based) formula.  Conduct food challenges in supervised medical setting (often inpatient).  Acute management: Consider intravenous fluids and methylprednisolone (1 gm/kg) during bouts

2nd Article: Retrospective chart review of 462 patients with FPIES from CHOP (Philadelphia).  Inclusion criteria: “classic reaction of prolonged vomiting and diarrhea that occurred 2-6 hours after ingestion of the food.”

Key findings:

  • Diarrhea occurred in about 50%.
  • Mean age of onset was 7 months for milk or soy compared with 12 months for grains
  • 43% of patients with milk-triggered FPIES react to soy as well
  • 42% of patients with a grain trigger react to two or more grains
  • More than 85% outgrew FPIES by 5 years of age.  35% outgrew their FPIES by age 2, 70% by age 3, and 80% by age 4.

Journal club discussion:

  • It was noted in the group discussion that FPIES in adults is most often triggered by shellfish/fish and eggs.
  • FPIES does not “run” in families. Though, atopic patients have increased risk. (As an aside: If you have diarrhea, it might be genetic –it might run in your jeans.)
  • The nomenclature of FPIES is problematic.  How come only ~50% have diarrhea if this is an “Enterocolitis” disorder?
  • Typically, trigger foods would not be reintroduced for a minimum of 12-18 months after last exposure/reaction.

Take home message: FPIES is a clinical diagnosis.  Be careful with oral challenges.

Related blog posts:

Looking Beyond the Headline for Ultra-Short Bowel Syndrome

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A quick glance at a recent study (JPGN 2014; 58: 438-42) suggests a favorable outlook for patients with ultra-short bowel syndrome (U-SBS). U-SBS has been defined as having a residual small bowel length <10 cm distal to the ligament of Treitz.  A more cynical definition by a colleague years ago was that U-SBS was when patients can fart and burp at the same time.

Looking at the details:  This study enrolled 11 patients into a prospective Italian database since 2000 and examined their outcomes.  Inclusion criteria included U-SBS diagnosed in the neonatal period (<28 days) and necessitating home parenteral nutrition at discharge.

The demographics note that these patients were bigger at birth and less premature than typical series of patients with SBS:

  • Only one of the patients had necrotizing enterocolitis as the sole underlying disease and six patients had volvulus.
  • All but two had ≥50% of their colons, with five having their entire colon.
  • All but one of these patients had gestational age ≥32 weeks and only two  patients had documented birth weight less than 2300 gm.

The authors note that these patients currently receive SMOFlipid as outpatients and Omegaven as inpatients.  All patients receive some enteral feedings.  Loperamide is used selectively.

Results:

  • Inpatient hospital care ranged from 23 to 104 days/year, but had improved during the last year of followup.
  • With >5 years of followup, 2 of the 11 patients had died.  One of these patients had severe intestinal failure associated liver disease (IFALD) despite use of Omegaven.
  • One patient underwent isolated intestinal transplantation.
  • No children in this series underwent a bowel-lengthening…”given the shortness of the residual small bowel, the gain of length after any procedure will not significantly improve absorption.”

Given their results, the authors note that despite recommendations for early referral for intestinal transplantation in patients with U-SBS, this may not result in a survival benefit.  They note a study by Pironi et al (Gut 2011; 60: 17-25) that showed that among 80 intestinal transplant candidates, 5-year survival was greater in those who were not transplanted.

Bottomline: This small cohort shows that certain populations of U-SBS may do well clinically for a long time with medical management. Caution should be used in extrapolating these results to SBS patients with different demographics.

Fructose Malabsorption and Recurrent Abdominal Pain

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Even before the popularity of a low FODMAPs diet, most pediatric gastroenterologists were aware that a significant number of children would develop pain if their diet included too much high fructose corn syrup.  A recent study shows that a breath hydrogen test (BHT) for fructose malabsorption may predict patients who will improve with a low-fructose diet (JPGN 2014; 58: 498-501).  Here’s a link to the abstract: 

Design: Retrospective study reviewed a single center experience.  Fructose BHT (1 g/kg fructose to max of 25 g) was administered to 222 patients who presented with recurrent abdominal pain.  An abnormal test was defined by a breath hydrogen >20 ppm over baseline.  If positive, families met with a nutritionist for instruction on a low-fructose diet.

Key result: 121 of 222 (54.5%) had positive BHT.  Of these 121 patients, 93 (77%) reported resolution of symptoms on a low-fructose diet.  Among those with a negative BHT, 54% reported resolution of symptoms without a low-fructose diet.

Take-home message: High fructose corn syrup and fructose malabsorption can contribute to abdominal pain; though, in clinical practice, a BHT is not needed to institute a trial of a low-fructose diet.

 

Therapeutic Inertia in U.S Neonatal Units (vis-a-vis Probiotics)

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“More than 90% of very low birth weight (VLBW) infants receive substandard care” could be the headline of a recent article/editorial (J Pediatr 2014; 164: 980-5 & 959-60).  Instead they are titled: “Cohort Study of Probiotics in a North American Neonatal Intensive Care Unit” and “Probiotic Supplementation in Preterm Infants: It is Time to Change Practice.”

In the article introduction, the authors state: “In 2011, faced with overwhelming evidence that probiotics could decrease NEC in preterm infants, and because there were no significant risks described in the extensive literature, we decided to introduce probiotics as routine care for the prevention of NEC.”

Methods: Prospective cohort study of infants at a single center NICU.  Examined rates of necrotizing enterocolitis (NEC) and death for 17 months before and after introduction of a probiotic (FloraBABY).  This probiotic (0.5 g) was mixed with water and administered just before milk once a day.  It was started at the first feeding and continued until the infant reached 34 weeks postmenstrual age.

Key findings:

  • Probiotics reduced NEC from 9.8% to 5.4% (OR for NEC 0.51)
  • Probiotics reduced combined outcome for NEC or death from 17% to 10.5% (OR 0.56).  Reduction in death by itself did not meet statistical significance.

Why, in 2012, were probiotics only used in 8-9% of VLBW?

Potential profits for probiotics are small which has limited studies of specific strains.  The probiotic, FloraBABY, in this study cost 11 cents per day in amount used; however, since the probiotic came in a tub, the actual cost was $12.79 for a 60-g tub for each patient.  Thus, manufacturers are unlikely to support studies to garner FDA approval.

Yet, there have been 22 randomized controlled trials published which “showed substantial benefits of probiotics and no adverse events.” A recently completed ProPrems trial (Jacob S et al, presented at 2013 PAS Annual Meeting) used a probiotic called ABC Dophilus Probiotic Powder for Infants.  This trial showed “a significant, >50%, reduction in NEC despite an incidence in their control patients of only 4.4%” and despite the fact that >95% of infants received breast milk.

“Good quality control and confirmation of the contents of the preparation are essential…There seems to be no further reason to delay the introduction of this evidence-based therapy in the NICU.”  The adoption of probiotics could avoid 2500 cases of NEC every year in North America.

The editorial notes that the evidence for probiotics is much better than many other therapies used in NICUs.  They note that some have argued that “the evidence that probiotics reduce mortality rates is as conclusive as that for surfactant for respiratory distress syndrome.”  A recent Cochrane review of 17 trials and >4900 VLBW infants showed that the RR of severe NEC for probiotics versus control was 0.41.

If people really understood this issue, there would be outrage over this issue.  In the U.S., there was recently extensive coverage over inaction about a faulty ignition switch which has been linked to at least 13 deaths.  The potential reduction in NEC and deaths with probiotics is likely much greater.

While the editorial recommends involving parent representative groups, I recommend discussing this issue with your neonatology colleagues along with your “quality care” team to find out what they are going to do about it.  Given the enormous costs in most NICUs, it is likely that each unit could self-fund a quality project (with consented patients) to provide probiotics to this vulnerable population.

Bottomline: Probiotics have excellent evidence as prophylaxis for NEC in VLBW infants.  Physicians need to advocate for their usage to “avoid years of therapeutic inertia.”

Related blog post: One More Day Syndrome & Necrotizing Enterocolitis …

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

Source Article: Methotrexate Safety

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A recent post (Monotherapy or Combination Therapy with Adalimumab) referenced an article indicating some potential concern for malignancy potential with methotrexate (Semin Arthritis Rheum 2014; 43: 489-97). Here’s a link to the source article/abstract:  Comparative cancer risk associated with methotrexate, other…

The authors conducted a comparative effectiveness study with cancer as an outcome in patients with rheumatoid arthritis (RA).  The final sample size was 6806 patients.  The most common drugs examined included methotrexate (n=1566) and TNF antagonists (n=3761). Other disease-modifying anti-rheumatic drugs (DMARDs) included other non-biologics (n=904), rituximab (n=167), and abatacept (n=408).

The authors note that with “the advent of newer DMARDs and combination therapy (this) has allowed more RA patients to lead more functional lives.  With this improvement in therapy, more attention is focused on the comparative risks and benefits of treatment.”

Key findings/discussion:

  • TNF antagonists were associated “with a reduced overall cancer risk versus methotrexate.” (HR 0.29).  Figure 2B, shows a plot with specific HR for various malignancies.  TNF antagonists had a HR of 0.15 for lymphoma.
  • Oncogenic potential of methotrexate was described almost 20 years ago, however, “its obvious clinical benefits have overshadowed malignancy concerns.”
  • “Our findings suggest that when examining the cancer risk associated with other DMARDs, combined methotrexate use must be factor into adjusted analyses.”

How does this translate to inflammatory bowel disease (IBD)?  While RA and IBD patients may have different risks for malignancy, this study suggests that patients receiving methotrexate therapy may have a low risk of malignancy.  The potential benefits of methotrexate therapy along with alternatives need to be weighed against this possible risk. Perhaps, this article may help reduce the concerns regarding anti-TNF therapy with regard to relative risk.

Related post:

Marriage, Divorce and Separation with Anti-TNF Therapy

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This review article (Inflamm Bowel Dis 2014; 20: 757-66) examines the question of whether and when anti-tumor necrosis factor (anti-TNF) agents can be stopped in Crohn’s disease (CD) patients in remission.  This topic is particularly helpful since this comes up frequently in clinical practice.

As recently as a few years ago, one expert advised me that starting an anti-TNF agent (like infliximab or adalimumab) was like getting married.  Once you committed, you stayed in that relationship indefinitely.  Of course, it is well-known that individuals get divorced.  In medical terms, I guess that would be the equivalent of developing antibodies to the anti-TNF agent or other adverse reactions.  Switching from one anti-TNF to another would be equivalent to marital infidelity.

So what does this review article say about all of this?  The article examines nine studies with a little more than 500 patients.  “Current evidence suggests that a group of CD patients, possibly 30% to 40% in clinical remission while on IM (immunomodulators) and infliximab can stop the latter and maintain clinical remission for a relatively long interval.  It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.”

If tempted to separate but not divorce anti-TNF therapy, the authors recommend, in addition to clinical remission, “normal colonoscopy (and/or normal surrogate markers of disease activity) should be adopted as a criterion when stopping therapy and during follow-up….As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues.  Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented…

If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (>1 year) remission and continuing the IM.  Such patients should be closely followed by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.”

Take-home message: Most patients are better off staying married to their anti-TNF therapy.

Also noted: Inflamm Bowel Dis 2014; 20: 742-56.  Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease.  This is a useful review with 103 references.

Superiority of Anti-TNF Therapy (Part 2)

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A recent blog (Superiority of Anti-TNF Therapy in Children | gutsandgrowth) described a recent article showing that kids treated with anti-TNF therapy at the time of diagnosis had improved outcomes compared to children who were treated with other medications.  In this day of multimedia, there is a video explaining the study which may be helpful for families and clinicians alike –here’s the link:  Dr. Michael Stephens discusses the research findings: .

An excerpt from the explanation with the video:

The current research study looks at outcomes and compares three different types of treatments. The first group receives anti-TNF therapy. The second group received immune modulating therapy. The third group received no treatment within the first three months. This study was an observational study and the choice of treatment was at the discretion of the physician. In order to correct for this factor, a statistical technique was used. Patients with similar characteristics were paired within the three groups . The results showed that patients who received the anti-TNF therapy had an improved outcome, such as a higher remission rate and some indications of improved growth, at one year. All three groups had improvements in weight and body mass index but only the anti-TNF group had improvements in linear growth.

Just the Beginning: Mutations in Very Early Onset Inflammatory Bowel Disease

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A recent study (Gastroenterol 2014; 146: 1028-39) indicates that mutations in tetratricopeptide repeat domain 7A (TTC7A) can result in a severe form of very early onset inflammatory bowel disease (VEOIBD).

After identifying a TTC7A heterozygote mutation in an infant by using whole exome sequencing of DNA, the authors subsequently identified 4 additional patients (2 siblings from 2 families) who also had loss of function mutations in VEOIBD.  Thus far, four of the five identified infants have died.

The manuscript has some terrific figures describing endoscopic/histologic characteristics, TTC7A genetic analysis, functional TTC7A enterocyte studies with immunofluorescence, impaired cell adhesion figure, tandem mass spectrometry, and a summary mechanistic figure (figure 6).  Hematopoietic stem cell transplantation has not been effective and might not work due to the enterocyte defect.

This study adds another VEOIBD gene mutation.  Previous mutations have involved in VEOIBD have included IL10RA/B, XIAP, ADAM17, NCF4, and NCF2/RAC2. The specific subtype matters as some defects may respond to stem cell transplantation.

Take-home message: there are a diverse number of pathways that can lead to VEOIBD.  Given the recent availability of whole exome sequencing, more mutations are sure to be identified soon.

Related blog post/link:

IL-10 and early onset IBD | gutsandgrowth In addition to the Toronto group (noted in this blog), a group in Boston with Harland Winter/CJ Moran is also interested in whole exome sequencing for VEOIBD patients.

Causes and Treatment of Very-Early Onset IBD –-this link is to the AGA Journals blog post on the same subject.

How Long Will Infliximab Work?

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Given the limited therapeutic options, the question of infliximab (IFX) durability in pediatrics is quite important.  One center has published its 10-year retrospective experience (Inflamm Bowel Dis 2014; 20: 606-13).

Inclusion criteria for the 188 patients included initiating IFX prior to age 21 years and patients who had a minimum of 1-year followup.

Demographics: Median age at diagnosis was 11 years for Crohn’s disease (CD) and 12 years for ulcerative colitis (UC). Indication for IFX due to steroid refractory disease was present in 42% of UC patients compared with 14% of CD patients.  Monotherapy was more common in UC patients, 65%, compared to 35% of CD patients.

Methotrexate was administered in 69 (44%) of CD patients at time of IFX with the majority (n=56) as oral treatment (low-dose <10 mg every week).  In addition, MTX was initiated after IFX induction in another 38 (24%).  Only 36 (23%) remained on IFX mono therapy throughout the duration of treatment in CD patients.

Key findings:

  • 88% of CD patients remained on IFX at 1 year, 80% at 2 years, and 72% at 5 years.
  • Only 7 of 157 CD patients were primary nonresponders.
  • 65 of 89 CD patients who did not achieve a sustained durable remission underwent dose escalation. 40 of 65 responded to dose escalation.
  • Of those who lost response to IFX, the majority were transitioned to adalimumab (ADA) and among this group, 82% remained on ADA treatment at last followup.
  • Among UC patients (n=31), 9 were primary nonresponders. At last followup, 41% (9) remained in a durable sustained response at last followup.
  • While the authors used MTX due to favorable effects on IFX pharmacokinetics (Arthritis Rheum 1998; 41: 1552-63), there was “not a significant difference in IFX durability or efficacy between this group and patients with CD on IFX monotherapy”
  • Availability of antibodies to infliximab (ATIs) and IFX trough levels were only assessed in a subset.  However, “we did see a significant difference in those that responded to dose intensification when ATIs were undetectable.”

Bottomline: The majority of CD patients can remain on IFX for >5 years.  Among those who lose response, adalimumab was a durable alternative.  A much lower durable response was evident with the subset of patients with UC.

Related blog post:

Also noted:

Inflamm Bowel Dis 2014; 20: 614-21. In this study of 78 youth with IBD, depressive symptoms warranting additional evaluation were present in 13% which was lower than in the community comparison group.  Disease severity was noted to be inactive in 63% and mild in another 18%.

Inflamm Bowel Dis 2014; 20: 495-501. This study showed that 25 children exposed to anti-TNFs prenatally for maternal IBD seemed to show good safety.  Immunologic investigation undertaken in 17 of the children was normal.  No control group limited the ability to determine if increased infections were present.

And, here’s a link to Mar-April Circle Newsletter from ImproveCareNow -topics include group medical appointments, parent working group, dieting with IBD, and includes link to self management handbook.

 

 

“Low quality of evidence; strong recommendation” for Probiotics in Gastroenteritis

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Recently a position paper on “Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN working group for probiotics and prebiotics” was published (JPGN 2014; 58: 531-39).

Two specific probiotics were recommended “strongly” but the working group describes the evidence for both as “low quality.”  This strikes me as odd.  The authors extensively reviewed previous studies and used the “GRADE” system to classify the quality of evidence and the category of recommendation.  There were 4 categories of quality of evidence: high, moderate, low and very low.  There were 2 possible recommendation categories: strong or weak.

The summary recommendations included the following:

  • Rehydration is the key treatment for AGE
  • Probiotics, overall, reduce diarrhea by approximately 1 day
  • However, probiotic effects are strain specific; findings from one probiotic cannot be extrapolated to another
  • The group recommends choosing probiotics with efficacy confirmed in well-conducted RCTs from a reputable manufacturer
  • Two specific recommended probiotics: Lactobacillus GG and Saccromyces boulardii

Take-home message: This article summarizes the available evidence for the use of probiotics in acute gastroenteritis.  Despite their classification as  “low quality of evidence,” the authors provide a strong recommendation for two probiotics (Lactobacillus GG and Saccromyces boulardii) as adjunctive therapy.

Related blog posts: