Mongerson -Phase II Data Available in NEJM

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Previously, this blog noted that a phase II study showed that Mongerson, an oral SMAD7 antisense oligonucleotide, had promising data for moderate-to-severe Crohn’s: An Oral Oligonucleotide in the Crohn’s Treatment Pipeline …

The study has now been been published: NEJM 2015; 372: 1104-13.  Among patients who received 40 mg and 160 mg of mongerson, remission (CDAI <150) at 15 days was achieved in 55% and 65% respectively compared to 12% for 10 mg dose and 10% for placebo group.

The associated editorial (pg 1166-67) notes that only 18% of the patients with elevated C-reactive protein and randomized to the 40 mg and 160 mg doses normalized these levels at the end of the treatment period.  Thus, further trials will need to look more closely at objective biomarkers.

Unrelated but interesting -from John Pohl & Bryan Vartabedian’s twitter feeds:  “Food Babe” Exposed as a Fraud

How Likely is Celiac Disease if My TTG Test Is Only a Little Bit Abnormal?

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A terrific celiac serology study (Gidrewicz D, et al.Am J Gastroenterol 2015; -advanced online publication doi: 10.1038/ajg.2015.87) helps answer questions about the utility of serology in making diagnostic decisions. (Thanks to corresponding author J Decker Butzner for sharing reference.)

Using consecutive samples in a laboratory database with 17,505 patients, the authors retrospectively examined the performance of the tissue transglutaminase (TTG), endomysial antibody (EMA) tests and the ESPGHAN celiac guidelines for nonbiopsy diagnosis of celiac disease.  Among this large cohort, 775 with positive TTG and 574 with a negative TTG were biopsied.

Key findings:

  • If the TTG >10-fold the upper limit of normal (ULN) along with a positive EMA and symptoms were present, 98.2% had biopsies consistent with celiac disease.
  • If the TTG was 3-10-fold-ULN along with positive EMA, then 75.7% had biopsies consistent with celiac disease.  The histology of celiac disease (CD) was present in only 40% of the TTG 3-10-fold ULN if EMA was negative.
  • If the TTG was 1-3-fold-ULN along with positive EMA, 52.2% had CD-positive histology, whereas CD-positive histology was evident in only 13.3% of TTG 1-3-ULN if EMA was negative.
  • IgA deficiency is common in CD (“1in 60 vs 1 in 700” in general population)

Implications & Take-home points:

  • The researchers note that the positive predictive value of TTG drops when the prevalence of CD in the testing population is lower.  Thus, in their population and most clinical practice where the prevalence is below 35-40%, the PPV of the TTG-based tests drops to <80%.
  • While TTG-based tests have high specificity, there are multiple medical conditions that can cause a false positive (additional reference below), including autoimmune diseases like diabetes mellitus, inflammatory bowel diseases as well as infections, and liver disorders.
  • Asymptomatic patients with low TTG titers and negative EMA may benefit from following celiac serology rather than proceeding immediately to intestinal biopsy.
  • Using ESPGHAN nonbiopsy criteria (symptomatic child, TTG ≥10 ULN, positive EMA, positive HLA typing), there were four patients whose initial biopsies were not consistent with CD.  Thus these criteria identified 98.2% accurately who did not need an intestinal biopsy.  One of these four developed CD subsequently.  To achieve 100% PPV for non biopsy, the authors note that one would need an EMA titer ≥1:80.
  • Study limitations: retrospective study, lack of standardization between TTG assays

Bottomline: EMA improves the PPV of TTG testing, especially when low titer elevations are noted.  TTG alone is a highly sensitive test “with a 99.4% negative predictive value” in this study.

Related study: “Serum Anti-Tissue Transglutaminase Antibodies Detected during Febrile Illness May Not be Produced by the Intestinal Mucosa” J Pediatr 2015; 166: 761-3.  This case report describes two children with abnormal TTG (one more than 20-fold ULN)) both were EMA-negative. No mucosal anti-TTG was identified using two immunoassays.

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NPR: “Should You Trust That New Medical Study?”

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A quick read from NPR: “Should You Trust That New Medical Study?”  No.

Here’s an excerpt:

As historian of science Naomi Oreskes says …, “What makes it news is that it’s new…My view would be that brand new results would be the most likely to be wrong.”

… We should infer the efficacy of a new drug or the benefits or harms of foods from a sample of studies, not a single new one. Of course, most people don’t have the time or the inclination to go through the exercise. When it comes to health, we want to believe in a new cure, for obvious reasons. Our skepticism must be doubled precisely to prevent being misled by hope. (Although hope and a positive attitude are known contributors to healing.) The responsibility, thus, rests with scientists and the media to promote the news carefully — and with the general consumer to keep the news in perspective.

Unrelated link: Nuts Associated with Improved Longevity (from NY Times)

Baseball Season!

Baseball Season!

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“Why Health Care Tech is Still So Bad” -NY Times

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Here’s the link on this thoughtful article: “Why Health Care Tech is Still So Bad”

This article highlights the problems including physicians distracted from patients due to data entry, problems with workflow, and alert fatigue. The author argues that we need to keep working on electronic health records; “the digitization of health care promises, eventually, to be transformative.”

Related blog posts:

 

How to Keep Enteral Feedings Safe

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As noted previously in this blog, enteral feedings are generally safe to administer overnight (Rest easy with enteral nutrition | gutsandgrowth).  Another study (Nutr Clin Pract February 2015 vol. 30, no. 1 128-133) agrees with this finding in both open and closed systems but with the caveat that addition of modular products to enteral feeds can result in unacceptable contamination.

Here’s the abstract:

Background: Temperature is known to affect bacterial growth, but current safety recommendations for enteral formula are based on studies conducted in thermoneutral environments, which are not representative of select burn intensive care units (ICUs) that are kept therapeutically hyperthermal. This project evaluated microbial growth in 3 enteral feeding systems: closed, open, and open with modular additives (modular tube feeding [MTF]) exposed to 2 different environments. Procedures: Product for each of the 3 systems was prepared and hung in both a thermoneutral (23.3°C) and a hyperthermal (32.5°C) ICU room. At baseline, 4 hours, and 8 hours, samples were plated and incubated overnight and the number of colony-forming units (CFUs) counted. Findings: In the thermoneutral and hyperthermal environments, there was no evidence of microbial growth in the open or closed feeding systems at any time point. The MTF exhibited baseline contamination with a median of 10 CFUs (95% CI, 8–16) and significant growth over time to 54 CFUs (95% CI, 20–230) by 8 hours in the thermoneutral setting. In the hyperthermal environment, the MTF showed baseline contamination of 390 CFUs (95% CI, 40–1600) and significant growth over time, with 30% of samples exhibiting contamination levels exceeding Food and Drug Administration standards by 4 hours and CFUs being too numerous to count by 8 hours. Conclusion: CFUs in enteral formula did not differ between open and closed feeding systems in either environment for up to 8 hours; however, the addition of modulars to open systems may result in an unacceptable risk of contamination in hyperthermal environments.

Other blogs related to enteral nutrition:

Probiotics -Another Positive Study for Prevention of Necrotizing Enterocolitis

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The topic of probiotics and necrotizing enterocolitis has been discussed several times on this blog (see some links below).  Here’s an abstract from a recent J Pediatr 2015;166: 545–51.

Objective

To test the efficacy of probiotic and prebiotic, alone or combined (synbiotic), on the prevention of necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants.

Study design

A prospective, randomized, controlled trial was conducted at 5 neonatal intensive care units in Turkey. VLBW infants (n = 400) were assigned to a control group and 3 study groups that were given probiotic (Bifidobacterium lactis), prebiotic (inulin), or synbiotic (Bifidobacterium lactis plus inulin) added to breastmilk or formula for a maximum of 8 weeks before discharge or death. The primary outcome was NEC (Bell stage ≥2).

Results

The rate of NEC was lower in probiotic (2.0%) and synbiotic (4.0%) groups compared with prebiotic (12.0%) and placebo (18.0%) groups (P < .001). The times to reach full enteral feeding were faster (P < .001), the rates of clinical nosocomial sepsis were lower (P = .004), stays in the neonatal intensive care unit were shorter, (P = .002), and mortality rates were lower (P = .003) for infants receiving probiotics, prebiotics, or synbiotic than controls. The use of antenatal steroid (OR 0.5, 95% CI 0.3-0.9) and postnatal probiotic (alone or in synbiotic) (OR 0.5, 95% CI 0.2-0.8) decreased the risk of NEC, and maternal antibiotic exposure increased this risk (OR 1.9, 95% CI 1.1-3.6).

Conclusions

In VLBW infants, probiotic (Bifidobacterium lactis) and synbiotic (Bifidobacterium lactis plus inulin) but not prebiotic (inulin) alone decrease NEC.

Related blog posts:

Preterm Neonatal Microbiota and Effect of Perinatal Antibiotics

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A recent study (Arboleya, S et al. J Pediatr 2015; 166: 538-44) provide sequential data regarding the intestinal microbiome in preterm infants in comparison to full-term infants; in addition, this study offers some insight into the changes that occur with perinatal antibiotics.

The researchers examined fecal samples at approximately 2 days of life, and then days 10, 30, and 90 in 27 preterm infants and 13 full-term babies. The study figures show the progression and changes of the microbiota over the first 90 days. In Figures 1, the profiles are the most similar between the full-term and preterm infants but there remains significant differences.

Key findings:

  • Preterm infants had higher initial percentage of Lactobacillaceae and reduced Bacteroidacease.
  • Perinatal antibiotics (including intrapartum antimicrobial prophylaxis) were noted to affect gut microbiota with increased Enterobacteriaceae organisms in these infants.

There were many confounding variables noted, including different diets, which make interpretation of the data difficult.  The full-term infants received exclusive breast milk whereas the preterm infants received mixed feedings.

A recent review (Houghteling, PD, Walker, WA.”Why Is Initial Bacterial Colonization of the Intestine Important to Infants’ and Children’s Health?” JPGN 2015; 60: 294-307) had a relevant figure:

From NASPGHAN Twitter Feed

From NASPGHAN Twitter Feed

Bottomline: Overall, Arboleya et al provide some additional baseline data but much more is needed to ascertain what factors will make children healthier –starting from before birth. The understanding of the microbiome is truly in its infancy.

Related blog posts:

 

Misdirection: False-postive Urine Cannaboid Screen due to Pantoprazole

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First of all, this post is not a joke for April 1st. But if you have a good story to tell, please feel free to comment -I’ll share a story at the bottom of this post.

A case report (Felton D et al. Pediatrics 2015; 135: 2014-16) makes a few useful points regarding testing for cannaboids in a patient admitted for cyclic vomiting syndrome.

  1. Intravenous pantoprazole could lead to a false-positive urine cannaboid screen.
  2. Cannabis hyperemesis syndrome should be included in the differential diagnosis for cyclic vomiting. (see previous blog: Think Like a Doctor -Another Reason for Cyclic Vomiting …)
  3. Don’t order every test on the differential diagnosis (my point -not the authors).

With regard to the final point, this particular case report describes a highly-impaired 13 year old with previous diagnoses of intrauterine stroke, global developmental delays, and seizures; she was nonverbal and nonambulatory.  Therefore, despite a positive urine screen, it is not surprising that the confirmatory testing for cannabis via gas chromatography-mass spectrometry was negative.

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On a side note, several years ago we had a little fun in the spirit of April 1st.  One of our neighbors had been complaining for years that they had not received ‘yard of the month’ but had lived in the neighborhood for more than 16 years. So, one year when they were out of town, we managed to borrow the ‘yard of the month’ sign, placed it in their yard, and snapped a picture.  With the collusion of a different neighbor who sends out the monthly announcement, our neighbors were informed of the recognition of their yard. It was definitely a good laugh.  At the same time, I’m a little paranoid about potential payback.

 

 

Predicting Response to Topical Steroids in Eosinophilic Esophagitis

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A recent study (Wolf WA, et al. Clin Gastroenterol Hepatol 2015; 13: 45-58) examined 221 patients in a retrospective cohort study to determine how effective topical steroids were in the treatment of eosinophilic esophagitis (EoE).  The authors studied these patients from 2006-2013; the majority received budesonide (63%) and the remainder received fluticasone; the typical dosing was 0.5 mg-1 mg twice daily and 440-880 mcg twice daily, respectively. 129 (58%) of the participants were >18 years.

Key findings:

  • 57% had histologic response with <15 eos/hpf
  • Refractory patients “were difficult to treat with dietary and second-line pharmacologic therapies, with less than half responding even after multiple second-line therapies.” The most successful second-line approach was diet: 6 of 16 (38%) had improved histology (<15 eos/hpf).  Higher doses of topical agents were effective in 2 of 14 (14%) and alternative topical agent was effective in 2 of 7 patients (29%).
  • Dilatation at the time of disease presentation (25% of the study cohort) correlated with poor clinical outcome.  Only 40% (20 of 50) had a histologic response.
  • High tissue levels of tryptase and eotaxin-3 increased the likelihood of a steroid response.

As this was a retrospective study, there were several weaknesses.

Take-home message: The findings from this large cohort show that more than 40% of patients did not have a favorable histologic response.  Some recent studies indicate that higher doses of steroids may be effective, but this may be influenced by the proportion of individuals with advanced fibrostenotic disease.

Related blog posts:

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.

Chicago's Bean

Chicago’s Bean

Lower Endoscopic Thresholds for Thrombocytopenia

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According to an advances in endoscopy report (Ross, WA. Gastroenterology Hepatology 2015; 11: 115-17), lower platelet thresholds are indicated for many endoscopic procedures.  The author works at MD Anderson Cancer Center in Houston.

Key points:

  • “We feel that the traditional threshold of 50,000 platelets/microliter that many doctors adhere to or aim for should be put aside, and a lower platelet threshold of perhaps 25,000 or 30,000 platelets/microliter should be employed for endoscopic procedures, including biopsies.“
  • “We found that therapeutic maneuvers could be performed to control bleeding.”
  • “This change would require fewer platelet transfusions to prepare a patient for endoscopy.”
  • Based on their published experience (Krishna SG, et al. “Saftey of endoscopic interventions in patients with thrombocytopenia.” Gastrointest Endosc 2014; 80: 425-34), the author notes that “polypectomy could probably be performed with a platelet count under 50,000/microliter, likely in the 30,000-40,000/microliter range, particularly if the polyp was small (<10 mm).”  They caution that cold snare technique may be safer in this setting but is not suitable for larger polyps.
  • Other preventative measures include stopping aspirin use, limiting the number and size of biopsies, and using non thermal means to help stop bleeding, such as clips or injections.
  • “Performing an endoscopic procedure in a patient with an extremely low platelet count, such as 5000/microliter, is associated with a high risk of bleeding.”

“If the procedure is just a simple biopsy, a platelet count of 25,000/microliter to 30,000/microliter should suffice.”

Take-home message: While the data that the author references is derived from adults, it is likely that in pediatrics that endoscopy, if needed, can be performed in patients with platelet counts less than 50,000/microliter.