Category Archives: Pediatric Gastroenterology Intestinal Disorder

Methotrexate Abstract: Subcutaneous vs. Oral Administration

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A recent abstract (Link: Gut doi:10.1136/gutjnl-2014-307964) indicates that there may be some advantages with subcutaneous methotrexate compared with oral administration, especially at the onset of treatment.

Here’s the abstract (thanks to KT Park for sharing this abstract on his twitter feed):

Efficacy of oral methotrexate in paediatric Crohn’s disease: a multicentre propensity score study

Background Oral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn’s disease (CD), especially children. Routes of administration have never been systematically compared in CD. We aimed to compare effectiveness and safety of orally (PO) versus subcutaneously (SC) administered MTX in paediatric CD.

Methods 226 children with CD treated with oral or subcutaneous MTX were included in a multicentre, retrospective 1-year cohort study (62% boys, mean age 13.8±2.8 years, 88% previous thiopurines). 38 (17%) were initially commenced on oral, 98 (43%) started subcutaneous and switched to oral and 90 (40%) were treated with subcutaneous only. Matching and ‘doubly robust’ weighted regression models were based on the propensity score method, controlling for confounding-by-indication bias. 11/23 pretreatment variables were different between the groups, but the propensity score modelling successfully balanced the treatment groups.

Results 76 children (34%) had sustained steroid-free remission with a difference that did not reach significance between the PO and the SC groups (weighted OR=1.72 (95% CI 0.5 to 5.9); p=0.52). There were no differences in need for treatment escalation (p=0.24), elevated liver enzymes (p=0.59) or nausea (p=0.85). Height velocity was lower in the PO group (p=0.006) and time to remission was delayed in the PO group (p=0.036; Fleming (0, 1) test).

Conclusions In this largest paediatric CD cohort to date, SC administered MTX was superior to PO, but only in some of the outcomes and with a modest effect size. Therefore, it may be reasonable to consider switching children in complete remission treated with subcutaneous MTX to the oral route with close monitoring of inflammatory markers and growth.

Related blog posts:

“Show Don’t Tell” –Colonoscopy Prep Instructions

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A recent study, summarized in this link– Gastroenterology and Endoscopy News, indicates that providing an 11 minute video with colonoscopy prep instructions was more effective than written instructions.  Not only were the cleanouts better, but this resulted in better outcomes including higher adenoma detection rate and higher rates of completed colonosocpy.

Here’s an excerpt:

Dr. Bearelly and his colleagues randomized 298 individuals scheduled for screening colonoscopy to receive either the practice’s usual written instructions, or to receive the paper handout plus an instructional video (right). The 11-minute video—burned on a disk —covers the same instructions as the written materials, but in an interactive format that depicts a typical patient asking questions of one of the practice’s doctors.

The quality of bowel preparation between the two groups differed significantly (P=0.0098). Cecal intubation was 96% in the intervention group compared with 89% in the control group, and the adenoma detection rate was 53% and 42% in the two groups, respectively.

Patients in the intervention group had a Boston Bowel Preparation Score (BBPS) of 6.99±1.87, whereas those in the control group had a score of 6.43±2.54, although the difference was not statistically significant. A BBPS of 6, with a minimum of 2 in each segment, was considered adequate.

Take-home message:  Video instructions for colonoscopy are worthwhile.  In pediatrics, variability in cleanout regimens is a limiting factor.

Related blog posts:

Looking More Closely at a Persistent Question

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Virtually everyday, families that I care for are trying to ascertain the link between their GI symptoms and the foods in their diet.  Many authoritative recommendations on irritable bowel have concluded that “food allergies (symptoms caused by an immune response) are rarely the culprit in IBS patients. Most IBS patients with food-related symptoms have food sensitivities or intolerances, which are not caused by an immune response.” (From Univ Virginia Irritable Bowel Diet PDF)

Whether the process is a sensitivity or an immune-reaction, many patients are quite sensitive to certain foods and many have had improvement with a low FODMAPs diet.

A much closer look at this problem with confocal laser endomicroscopy (CLE), in a pilot study (Gastroenterol 2014; 147: 1012-20), has shown measurable changes within five minutes of a food challenge that takes place during an endoscopy.  In this study, the researchers examined 36 patients with IBS who had suspected food intolerance and 10 control patients with Barrett’s esophagus.  Then during an endoscopy, the researchers used provoking solutions of cow’s milk, wheat, yeast, or soy.  The subjects had CLE before and after the challenges. To enhance visualization of changes, subjects had fluorescein dye injected intravenously prior to examination of the duodenum.

Results

  • In 22 of 36 patients, the challenges were considered positive.  These patients had mucosal changes including increase in intraepithelial lymphocytes, followed by disruption of the villi tips/shedding of cells, then fluorescein leakage into the lumen.
  • None of the control patients exhibited these changes.
  • 19 of 22 patients with positive challenges had a >50% reduction, after 4-weeks, in symptom score with individualized diet based on inciting antigen.

Bottomline:

This provocative study indicates that subtle mucosal changes can occur in a number of IBS patients in a quick and direct response to food challenges.  Perhaps when we look closer with technologies like CLE we will find more answers as to why certain foods provoke symptoms in adults and children with IBS.

Related blog posts:

Also noted –web-based information on gastroparesis:

“There is No ‘Healthy’ Microbiome”

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While thinking about what you might eat later today and pondering how this may affect your GI tract, perhaps a recent editorial may provide some reassurance.

A recent editorial provides an insightful view regarding a ‘healthy’ microbiome.  Despite all of the publications on this subject (and the numerous posts on this blog), there is not a one-size fits all microbiome.

Here’s the link  “No Healthy Microbiome” and an excerpt:

These microscopic partners help us by digesting our food, training our immune systems and crowding out other harmful microbes that could cause disease. In return, everything from the food we eat to the medicines we take can shape our microbial communities — with important implications for our health. Studies have found that changes in our microbiome accompany medical problems from obesity to diabetes to colon cancer.

As these correlations have unfurled, so has the hope that we might fix these ailments by shunting our bugs toward healthier states. The gigantic probiotics industry certainly wants you to think that, although there is little evidence that swallowing a few billion yogurt-borne bacteria has more than a small impact on the trillions in our guts….

But how can you tell when it needs replacing? A bloom of C. difficile is an obvious problem, but most other communities are not so easily classified. The microbiome is a teeming collection of thousands of species, all constantly competing with one another, negotiating with their host, evolving, changing. While your genome is the same as it was last year, your microbiome has shifted since your last meal or sunrise.

We need to start thinking about it as an ecosystem, like a rain forest or grassland, with all the complexities that entails. And just as the gorillas and leopards of African forests differ from the wolves and moose of American ones, so, too, do microbiomes vary around the world.

Clostridium difficile/Fecal Microbiota Transplantation Video

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I have been a fan of OpenBiome (www.OpenBiome.org).  Their website provides a nice ~3 minute explanation of Clostridium difficile and the rationale for fecal microbiota transplantation (FMT). Here’s the link: C diff FMT video

In addition to this video, their website has a lot of information (for families and clinicians) about how to obtain and use safe, screened stool products. Here’s their background information (from their website):

Why we’re here:

We founded OpenBiome, a nonprofit 501(c)(3) organization, after watching a friend and family member suffer through 18 months of C. difficile and 7 rounds of vancomycin before finally receiving a successful, life-changing Fecal Microbiota Transplantation (FMT). The remarkable efficacy of this treatment and the great lengths required to receive it convinced us that we needed to help expand access. After many discussions with local clinicians and the FDA, we launched OpenBiome in 2012 to make FMT faster and easier for patients and doctors alike.

What we do:

We work with clinicians to make FMT easier, cheaper, safer and more widely available. We do so by providing hospitals with screened, filtered, and frozen material ready for clinical use. This service eliminates the time, staff, protocols, and facilities needed to screen and prepare material from new donors for each treatment. With OpenBiome, all that’s needed to deliver FMT is a doctor and an endoscope.

Related blog posts:

Cheap Technology for Button Battery Ingestions

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Typical Button Battery

Typical Button Battery

An NPR report regarding “the results of .. experiments published Monday in the Proceedings of the National Academy of Sciences show that a prototype shield is effective at keeping small, 11 millimeter batteries from damaging the esophagus after being swallowed.”  This would be worthy endeavor to pursue.  The larger buttons (20 millimeters in diameter) “are particularly dangerous. One out of 8 children [under 6 years old] who swallow this larger battery are going to have a serious debilitating complication.”  Here’s the link: Battery Shield

Here’s an excerpt regarding the shield:

Microscopic metal particles are embedded in the shield, which is a millimeter thick. When a battery is inserted into a device, the pressure from the device’s cover or a spring that holds the battery in place pushes the metal particles together. The shield then acts like a switch, conducting electricity.

When the battery is free, floating down a child’s esophagus, for instance, there’s not enough pressure to make the microparticles smush together. The shield then acts as an insulator…

The shield’s material is commercially available and currently used in touch-screen devices where a gentle press of a fingertip can complete a circuit.

Related blog posts:

 

"Great Power" for Damaging an Esophagus

“Great Power” for Damaging an Esophagus

NASPGHAN Notes –Last Word for this Year

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This blog entry has abbreviated/summarized several presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

IBD Treatment: Targets for the Modern Age –Eric Benchimol (Children’s Hospital of Eastern Ontario)

Goal: Review mucosal healing and best targets to measure to predict prognosis

Treat-to-target:

  • Regular assessment of disease activity using objective outcome measures.
  • Adjust treatment if not accomplishing goal.
  • Proven helpful in rheumatoid arthritis, hypertension, diabetes, and hypercholesterolemia.

Old targets:

  • “Clinical remission”
  • “Feeling better”
  • Indices: PCDAI, CDAI, Harvey-Bradshaw
  • Problem: Active disease is not well-predicted by symptoms or laboratory markers
  • 2nd Problem: Active symptoms not always due to active IBD (could be due to functional complaints)
  • PUCAI score in ulcerative colitis does reflect ulcerative colitis severity fairly well

New Targets

  • High correlation with outcomes
  • Cost-effective
  • Available

Is mucosal healing achievable?   If you were scoped and adjustments made in therapy, then much higher rate (HR >4) of remission. Bougen, Clin Gastroenterol Hepatol 12: 978.  Endoscopy may be best way to assess mucosal healing.  Since it is invasive, efforts have been made to identify surrogate markers.

Treat-to-Target Algorithm

Treat-to-Target Algorithm

Surrogate Markers

  • Ultrasound –can be useful but operator-dependent
  • MRE had 83% accuracy for endoscopic remission: Gastroenterol 2014; 146: 374.
  • Calprotectin not as accurate in children? Am J Gastroenterol 2014; 109: 637. Sensitivity high 97%, specificity for remission 68%
  • CRP –if elevated, higher risk of complications or surgery. However, sensitivity is much lower for disease activity than calprotectin/imaging studies for active disease
  • Drug levels. Therapeutic IFX trough levels (and adalimumab) are highly predictive of mucosal healing.

Bottomline (my interpretation): Resolution of clinical symptoms and improvement in bloodwork is not good enough.  When/timing to assess with sensitive surrogate markers is still uncertain.  In many patients, endoscopy is needed to assure adequate improvement; however, in others, a followup imaging study (eg. MRE) or sensitive stool assays may be the best approach.

A related story (from AGA’s Today in Medicine email feed & pointed out to me by Ben Gold) indicates that estimation of clinical symptoms is not accurate:

Survey Suggests Severity Of IBD Is Underestimated By Gastroenterologists.

MedPage Today (10/31, Walsh, 186K) reports that survey results presented at a medical conference indicate that “the severity of inflammatory bowel disease is significantly underestimated by gastroenterologists.” Researchers found that “a total of 55% and 67% of physicians who participated in a web-based survey rated cases of Crohn’s disease and ulcerative colitis as being mild when they were actually moderate.” Meanwhile, “for case studies that represented severe disease, 76% and 81% of the physicians gave ratings of either moderate or mild for Crohn’s disease and ulcerative colitis, respectively.”

 

Related blog posts:

Risk Stratification in Pediatric IBD: Are we there yet? Jeffrey Hyams (Connecticut Children’s

Initially, Dr. Hyams described the exploding head syndrome; many attendees might have thought they had this due to information/”big data” overload, but this syndrome is a sleep disorder/parasomnia event.  Here’s a link to the image from his talk.  Then, Dr. Hyams reviewed data on risk stratification:

  • Mutations: Some genetic mutations are associated with disease severity
  • Still needed: specific pediatric data
  • Microbiome: Some profiles associated as prognostic factors in pediatric RISK study
  • Early anti-TNF associated with improved outcomes (using propensity analysis) Gastroenterol 2014; 146: 383.

Bottomline: Not there yet with risk stratification. Many factors environmental, genetic susceptibility, immune response, and treatment need to be sorted out with “big data.”

Key Clinical Questions for your practice at this time:

  • Does this patient have known risk factors for doing poorly?
  • Am I using current therapies properly?
  • What is the risk of undertreated disease? This needs to be considered with discussion of safety of IBD meds.

Cross Examination of Cross-Sectional Imaging in IBD –Sudha Anupindi (Radiology/CHOP)

  • For the most part, barium studies discouraged (eg. UGI/SBFT) by speaker; radiation ~1 mSv.
  • CT (conventional) widely available and easy –if needed urgently/middle of night.

Initial presentation: imaging of choice

  • MR enterography –no radiation, better contrast resolution, best for perianal disease, able to evaluated peristalsis. Two limitations: cost, interpretation
  • CT enterography –fewer motion artifacts (0.6 seconds), lower cost, increased availability, better spatial resolution radiation reduced with current technology at most Children’s hospitals: 1-2 mSv

Abdominal ultrasound holds promise as alternative imaging with lower cost.

 

More NASPGHAN Meeting Notes: IBD Hot Topics

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“The best preparation for tomorrow is to do today’s work superbly well”  –William Osler (quote cited in NEJM 2014; 371: 1565-66).

This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

For me, these lectures were a useful review and represent an effort to achieve Osler’s objective of doing superb work.  If I had to choose a single issue that may affect my practice: when initiating infliximab, consider checking week 14 trough levels of infliximab and optimize dosing.

The role of the microbiome in IBD   –Subra Kugathasan (Emory)

This was a terrific lecture though with some overlap with a number of other presentations at the meeting. The lecture reviewed how to interpret microbiome studies and what we are learning from these studies with regard to inflammatory bowel disease.

Enteral Nutrition and Microbiota –conclusion:

  • EN may work by suppressing the entire microbiota in Crohn’s disease thus lowering antigenic effect to the gut
  • Some microbes may be pro-inflammatory and others pro-fibrotic
  • Chicken and egg: preliminary evidence suggests that dysbiosis is probably a preceding predisposing factor rather than due to the consequence of having inflammatory bowel disease.

The Role of Drug Monitoring in Inflammatory Bowel Disease –Jennifer Strople (Children’s Hospital of Chicago)

TPMT Testing/thiopurine metabolite monitoring

  • goal: minimize adverse effects and optimize thiopurine dosing.
  • those with lower (but not absent) activity may be best candidates for treatment with azathioprine/6-mercaptopurine (thiopurines).
  • normal TPMT testing does NOT exclude complications like bone marrow suppression or pancreatitis.
  • obtaining TPMT at baseline is cost-effective
  • goal of 6-thioguanine level of >235 (odds ratio favorable of responding to/remission with treatment)
  • drug levels: allows monitoring for noncompliance; limitation of costs and using levels inappropriately. Routine testing “has no role in patients who are doing well on acceptable doses of thiopurines”
  • younger patients often need higher doses

Monitoring for anti-TNF Therapy

  • Loss of response most common in first year of therapy.
  • For infliximab (IFX), IFX trough levels >3 mcg/mL predicted sustained response. Gut 2014; 63: 1721.
  • Week 14 IFX levels predict outcomes:
IFX Levels at 14 weeks

IFX Levels at 14 weeks

  • Preliminary data with ulcerative colitis shows that troughs >3.7 mcg/mL increases likelihood of mucosal healing and remission.
  • Undetectable trough levels of IFX associated with increased risk of colectomy with ulcerative colitis Gut 2010 59: 49
  • If a patient develops high levels of anti-drug antibodies (ADAs), this makes likelihood of response to medications unlikely. The specific ADA level is helpful; high levels of drug antibody are particularly problematic. If low levels of drug without ADAs, then increasing dose is typically effective.
IFX Algorithm

IFX Algorithm

  •  If losing response to therapy and if active disease is present, then check drug concentration. If subtherapeutic with no ADAs or low ADAs, dose escalation with or without immunomodulator is indicated.
  • If subtherapeutic with high ADA, then change drug
  • If therapeutic level, then may need to change to different anti-TNF or drug class.

Related posts on this topic:

Debate: Immunomodulators versus Biologic agents 

  • James Markowitz –consider starting with immunomodulators
  • Maria Oliva-Hemker –consider starting with biologics

In the face of the “Biologic Tsunami,” Dr. Markowitz suggested –“Don’t throw the baby out with the bathwater”

  • Reviewed infliximab data, and adalimumab data. 1-year remission rates 50-60%.
  • Durability of infliximab may be influence by immunomodulators (IMs): patients who had IM prior to IFX had better durability of response:  45% durability in those who had no IM prior to biologic, 53% durability in those who had IM for ❤ months, 66% durability in those who had IM for >6 months prior to IFX.
  • Adult data showing lack of efficacy with IMs influenced by different characteristics compared with children (eg. different disease location, ~40-50% of adults were smokers)
  • Reviewed toxicity of IMs and biologics
  • Children with severe disease do best with “early infliximab.”
  • IMs with 40-60% efficacy over 18 months and then relatively stable.
  • In Dr. Markowitz’ practice, IM use: girls receive thiopurines and boys receive methotrexate

Biologics –important to start before disease phenotype changed to stricturing/penetrating disease. (See images below)

Related posts:

Early anti-TNF -RISK Cohort

Early anti-TNF -RISK Cohort

 

Long Term Risk of Stricturing (Cosnes et al)

Long Term Risk of Stricturing (Cosnes et al)

“The future of gastrointestinal disease and symptom monitoring: biosensor, E-portal, and social media”

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At this year’s NASPGHAN meeting, the keynote lecture was given by Brennan Spiegel.  (Brennan Spiegel, MD (@BrennanSpiegel) | Twitter) This was a great talk!

This blog entry has abbreviated/summarized the presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Challenges in healthcare:

  • Time with patient is limited/poorly-timed in comparison to health care needs.
  • Care is reactive rather than proactive.
  • Care is expensive.

We spend all our time within walls of our clinic/hospital, but patients spend 99% time outside

 

How do we tailor care to the individual and make it more cost-effective? How do we get there?  Potential/Emerging Tools:

    • Patient provider portals (including mobile)
    • Social media
    • Wireless biosensors

 

Key question for patients: What is the most important goal for you/your family today?

How to improve communication with family? Electronic medical records often designed for billing rather than educating

MyGiHealth website/soon-to-be-app.  Here’s a link to YouTube video introduction.

  • HISTORY: Trained computer to interview patient re: abdominal pain –where, timing, risk factors for H pylori, etc.
  • Symptoms and severity: constipation, abdominal pain, gas/bloating, heartburn, diarrhea, dysphagia, incontinence, nausea/vomiting (Promise scales –percentiles).
  • Computer history looked better than history by physician (example below with fictional patient). If history obtained prior to physician coming into room, this would allow physician more time to communicate with patient rather than documenting (Related post: Aptly titled “The Cost of Technology” | gutsandgrowth)
  • Man vs Machine (Spiegel in press Am J Gastro 2014). History performed well with regard to billing complexity and completeness.
  • THIS IS COOL!
  • Physician still needed to analyze information and make diagnosis/treatment plan.
  • Also website/app with EDUCATION applicable to patient.
History by computer outperformed physicians

History by computer outperformed physicians

Obtaining information outside the confines of the office can help overcome Hawthorne effect. (Related blog post: Checklists -Helpful? Overhyped? Hawthorne Effect …). Passive vs Active monitoring.

Twitter: “What you say on twitter may be seen by everyone all over the word instantly”

  • Tool for epidemiologic data.
  • Marketing/advertising
  • Recruiting for clinical studies
  • Measure consumer sentiment
  • Educate patients/providers
  • Forge patient affinity groups
  • Monitor patients for clinical practice
  • Help to manage and direct care

Mayo clinic is studying the impact of social media.

Example of patients initiating research. “Spontaneous Coronary Artery Dissection: A Disease-Specific Social Networking Community-Initiated Study” Lead author: Marysia Tweet

Biosensors:

  • “91% of people keep their phone within 3 feet of themselves 24 hours a day.”
  • Can be used to track intake of food, air quality, movements etc
  • Current sensors: Fit bit, amigo (?sp), shine (?sp), Zeo (for sleep) others.
  • Fitbit: Calories, distance, active time, sleep time
  • More advanced sensors for athletes. Stride dynamics can predict marathon winner at mile 16!
  • Wireless sleep (eg. Zeo) monitor equivalent to formal sleep study
  • Q Sensor –can measure stress: physical ,cognitive, emotional (watching horror movie)
  • Hapi fork –can tell if you are eating too fast (correlated with BMI)
  • Proteus –monitors intake
  • Propeller –monitors MDI use for asthma (FDA approved)
  • AbStats Digestion Sensor –adheres to abdomen and can provide neurogastroenterology data. Green light –will tolerate feeds, Yellow light –will tolerate clears

75,000 health apps available at this time.

Recommended Reading by Dr. Spiegel: The Creative Destruction of Medicine by Eric Topol.  The Creative Destruction of Medicine: How the Digital …

 

Parenteral Lipids & Cholestasis –a Little More Data

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A recent publication in JPGN indicates that resuming low dose soy-based parenteral lipid can be effective in patients (n=7) whose cholestasis had resolved on a fish oil-based parenteral lipid. It does not resolve the larger question of whether fish oil-based parenteral lipids are truly more effective than soy-based parenteral lipids (see previous blog links below).

Here’s the abstract:

Objectives: Intestinal failure associated liver disease (IFALD) contributes to significant morbidity in pediatric intestinal failure (IF) patients. However, the use of parenteral nutrition (PN) with a fish oil-based IV emulsion (FO) has been associated with biochemical reversal of cholestasis and improved outcomes. Unfortunately, FO increases the complexity of care: as it can only be administered under FDA compassionate use protocols requiring special monitoring, is not available as a 3-in-1 solution and is more expensive than comparable soy-based lipid formulation (SO). Due to these pragmatic constraints a series of patient families were switched to low-dose (1 g/kg/day) SO following biochemical resolution of cholestasis. This study examines if reversal of cholestasis and somatic growth are maintained following this transition.

Methods: Chart review of all children with IFALD who switched from FO to SO following resolution of cholestasis. Variables are presented as medians (interquartile ranges). Comparisons performed using Wilcoxon signed-rank test.

Results: 7 patients aged 25.9 (16.2,43.2) months were transitioned to SO following reversal of cholestasis using FO. At a median follow up 13.9 (4.3,50.1) months there were no significant differences between pre- and post-transition serum alanine and aspartate aminotransferases, direct bilirubin, and weight-for-age z-scores. Due to recurrence of cholestasis, one patient was restarted on FO after four months on SO.

Conclusions: Biochemical reversal of IFALD and growth were preserved after transition from FO to SO in 6/7 (86%) patients. Given the challenges associated with the use of FO, SO may be a viable alternative in select home PN patients.

Related blog posts: