Ulcerative Colitis with Questionable Response to Fecal Transplant

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Fecal microbiota transplantation (FMT) is not going to be a “magic bullet” for most patients with inflammatory bowel disease. So far, it is unclear whether FMT works at all.  A recent study (full text link: Rossen NG et al. Gastroenterol 2015; 145: 110-8) with only 37 patients echo that experience. Here is the abstract:

Background & Aims

Several case series have reported the effects of fecal microbiota transplantation (FMT) for ulcerative colitis (UC). We assessed the efficacy and safety of FMT for patients with UC in a double-blind randomized trial.

Methods

Patients with mild to moderately active UC (n = 50) were assigned to groups that underwent FMT with feces from healthy donors or were given autologous fecal microbiota (control); each transplant was administered via nasoduodenal tube at the start of the study and 3 weeks later. The study was performed at the Academic Medical Center in Amsterdam from June 2011 through May 2014.

The composite primary end point was clinical remission (simple clinical colitis activity index scores ≤2) combined with ≥1-point decrease in the Mayo endoscopic score at week 12. Secondary end points were safety and microbiota composition by phylogenetic microarray in fecal samples.

Results

Thirty-seven patients completed the primary end point assessment. In the intention-to-treat analysis, 7 of 23 patients who received fecal transplants from healthy donors (30.4%) and 5 of 25 controls (20.0%) achieved the primary end point (P = .51). In the per-protocol analysis, 7 of 17 patients who received fecal transplants from healthy donors (41.2%) and 5 of 20 controls (25.0%) achieved the primary end point (P = .29). Serious adverse events occurred in 4 patients (2 in the FMT group), but these were not considered to be related to the FMT. At 12 weeks, the microbiota of responders in the FMT group was similar to that of their healthy donors; remission was associated with proportions of Clostridium clusters IV and XIVa.

Conclusions

In this phase 2 trial, there was no statistically significant difference in clinical and endoscopic remission between patients with UC who received fecal transplants from healthy donors and those who received their own fecal microbiota, which may be due to limited numbers. However, the microbiota of responders had distinct features from that of nonresponders, warranting further study. ClinicalTrials.gov Number: NCT01650038.

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Cumberland Island

Cumberland Island

 

Preventing Vertical Transmission of Hepatitis B with Telbivudine

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Briefly noted:

Wu Q et al. Clin Gastroenterol Hepatol 2015; 13: 1170-76.  This was a prospective study of 450 Hepatitis B e antigen-positive pregnant women with HBV DNA levels greater than 10 to the 6th IU/mL.  279 women received telbivudine 600 mg daily starting between 24 to 32 weeks of gestation until delivery or up to a month thereafter; this treatment group was compared to 171 controls women unwilling to take the medication. All infants received vaccinations after birth along with hepatitis B immune globulin. None of the infants in the treatment arm acquired hepatitis B (negative HBsAg at 6 months) compared with 14.7% of infants in the control arm who were positive for infection.  no serious adverse effects were noted in the women receiving telbivudine or their infants.

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Omega-3 Fatty Acids and Nonalcoholic Fatty Liver Disease

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A recent study (Janczyk W. J Pediatr 2015; 166: 1358-63; editorial 1335-6) examines whether omega-3 fatty acid supplement would be helpful for overweight/obese children with nonalcoholic fatty liver disease (NAFLD).  This randomized controlled trial had 64 patients complete the study; the median age of enrolled patients was 13 years.

Free Full Text Article: Omega-3 Fatty Acids Therapy in Children with Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial

The treatment cohort received doscosahexaenoic acid (DHA) and eicosapenatenoic acid (EPA) at a dose of 450-1300 mg/day.

Key finding:

  • After 6 months, omega-3 fatty acid supplementation did not increase the number of patients with decreased ALT levels and it did not affect liver steatosis on ultrasound.

The editorial reviews a previous positive study for DHA supplementation from Italy (n=60) but notes that other larger trials in adults have not shown efficacy of omega-3 fatty acids (Gastroenterol 2014; 147: 377-84.e1, Hepatology 2014; 60: 1211-21). It could be that much longer studies will be needed to determine whether omega-3 fatty acids will be helpful.

Take-home message: Overall, the sum of these studies indicates that supplementation with omega-3 fatty acids has not been shown to be effective for NAFLD and it is not likely to be a significant breakthrough.  Even if it were shown to help modestly, would pediatric patients be placed on therapy indefinitely?

Briefly noted:

Kusters DM et al. “Efficacy and Safety of Ezetimibe Monotherapy in Children with Heterozygous Familial and Nonfamilial Hypercholesterolemia” J Pediatr 2015; 166: 1377-84.  Ezetimbe (10 mg), a cholesterol absorption inhibitor, lowered LDL by 27% after 12 weeks from baseline. It was well-tolerated

New Therapy for Celiac Disease: Larazotide Acetate

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A recent randomized controlled trial study (Gastroenterol 2015; 148: 1311-9) examined the effectiveness of larazotide acetate in 342 adults with Celiac disease (CD) who had ongoing symptoms despite the use of a gluten-free diet for at least 12 months.

Larazotide acetate is a locally acting, nonsystemic 8-amino acid oral peptide which is a tight junction (TJ) regulator.  “Larazotide acetate appears to prevent opening of intestinal TJs by promoting TJ assembly and actin filament rearrangement, which prevents gluten from reaching the intestinal submucosas and triggering an inflammatory response.”

Screen Shot 2015-06-01 at 8.35.51 PM

Patients received either placebo, 0.5 mg, 1 mg, 2 mg three times daily. The majority of patients had normalized serology at the start of the study.  Key findings:

  • “The 0.5 mg dose showed a 26% decrease in celiac disease patient-reported outcome symptomatic days (P =.017), a 31% increase in improved symptom days (P =.034), a 50% or more reduction from baseline of the weekly average abdominal pain score for 6 or more of 12 weeks of treatment (P =0.022), and a decrease in the nongastrointestinal symptoms of headache and tiredness (P =0.010).”
  • The 1- and 2-mg doses were no different from placebo for any end point.
  • Safety was comparable to placebo.

The authors state that is unclear why the higher doses were not effective “but may involve peptide aggregation … reducing activity in vivo.”

Bottomline: There would be a benefit for an adjunct to a gluten-free diet due to the difficulty in adherence and due to ongoing symptoms in some despite the use of a GFD; in some cases, symptoms may be induced by inadvertent deviation from GFD.  More data is needed to determine if larazotide acetate will be useful in this role.

Related blog post: Good Educational Two Minute Celiac Video | gutsandgrowth

Data on Drug-Induced Liver Injury

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Two recent studies provide complementary information regarding the causes and consequences of Drug-Induced Liver Injury (DILI).:

  • Chalasani N, et al. Gastroenterol 2015; 148: 1340-52.
  • Goldberg DS, et al. Gastroenterol 2015; 148: 1353-61.

The first study looked at 899 patients with DILI in the DILI Network which is a consortium of several academic institutions funded by the US National Institutes of Health.  Antimicrobials were the most commonly implicated agents (408 cases); however, dietary/herbal supplements were another common cause (145 cases).  Top 10 individual agents:

  • Amoxicillin-clavulanate (Augmentin) (n=91)
  • Isoniazid (n=48)
  • Nitrofurantoin (n=42)
  • Sulfamethoxazole/trimethoprim (n=31)
  • Minocycline (n=28)
  • Cefazolin (n=20)
  • Azithromycin (n=19)
  • Ciprofloxacin (n=16)
  • Levofloxacin (n=13)
  • Diclofenac (n=12)

Key findings:

  • Overall, 10% of patients with DILI died or required liver transplantation.
  • 18% developed chronic injury pattern; this was more common in patients with a cholestatic liver injury.
  • Mortality was high in patients with DILI and concomitant severe skin reactions.  Causative agents of DILI with either Stevens-Johnson Syndrome or Toxic epidermal necrolysis included azithromycin (n=2), lamotrigine (n=3); and one case for each of the following: moxifloxacin, diclofenac, carbamazepine, nitrofurantoin, and possible cephalexin (patient rec’d lamotrigine as well)
  • Preexisting liver disease increased the likelihood of mortality (16% versus 5%)

The second article, a retrospective cohort study using data from >5 million covered individuals over a 7-year span from Kaiser Permanente Northern California, identified 62 inpatients categorized as having definite or possible acute liver failure (ALF).  In this cohort, 32 (52%) had DILI.  Leading agents of DILI-ALF:

  • Acetaminophen n=18
  • Herbal/dietary supplement n=6. Chinese herbals (n=2), pine needle tea, saw palmetto, one unspecified herbal.
  • Antimicrobials n=2

Bottomline: Antibiotics and herbal supplements, both of which are often used without apparent benefit, can lead to liver failure

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Soapes Creek, Atlanta

Soapes Creek, Atlanta

Would Medical Marijuana Meet the Threshold for FDA Approval?

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For most conditions –the answer is no.  A recent study was reviewed by several media outlets including the LA Times.  Here is an excerpt:

A comprehensive review of dozens of clinical trials that have tested medical marijuana for 10 conditions finds that there’s very little reliable evidence to support the drug’s use. The review, by an international team of researchers, was published Tuesday in the Journal of the American Medical Assn.

Patients who use medical marijuana to treat chronic neuropathic pain or cancer pain would probably have the least to fear from an FDA review. The JAMA study considered 28 studies involving 2,454 patients and concluded that there was “moderate-quality evidence” from at least a dozen studies showing that cannabinoids – chemicals in marijuana that produce pharmacologic effects inside the body – reduced pain in such patients by modest amounts….

The other condition for which medical marijuana proved useful was muscle spasticity in people with multiple sclerosis. After assessing 14 studies with 2,280 patients, the JAMA authors determined there was “moderate-quality evidence” to support its use in these patients, although many of the studies reported improvements that weren’t quite big enough to qualify as statistically significant…

One of the things the studies showed most clearly is that people who use medical marijuana had a “much greater risk” of side effects, including serious problems like kidney, liver and psychiatric disorders. The most common adverse effects included dizziness, confusion and disorientation,  according to the JAMA report…

The authors, from the Yale University School of Medicine, lamented the fact that state approval of medical marijuana had been based on “low-quality scientific evidence, anecdotal reports, individual testimonials, legislative initiatives, and public opinion.”

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Zoo Atlanta

Zoo Atlanta

What is an Entrustable Professional Activity?

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It has been said that the difference between a haircut and a coiffure is about $30.

When I was reviewing an article (Rose S, et al. Gastroenterol 2014; 147: 233-42 -thanks to Ben Gold for this reference), the previous joke came to mind.  While I’m sure that there has been a lot of hard work to improve the effectiveness of gastroenterology fellowship training, I find the term “entrustable professional activity” (EPA) to be a strange term to define specific goals for educational assessment and competency.

Bottomline: For those in training and for those doing the training, entrustable professional activity is the new buzzword.

Briefly noted -unrelated studies:

Wang H et al. J Pediatr 2015; 166: 1404-9.  This study examined 4976 among the “Children of 1997,” a prospective population-representative Chinese birth cohort.  They “did not find adiposity [to] be a factor in the development of emotional/behavioral problems in early adolescence” (age 11 years).

Niemi AK, et al. J Pediatr 2015; 166: 1455-61. Treatment of methymalonic academia by liver or combined liver-kidney transplantation. This study identified fourteen transplant recipients; the 6 who had isolated liver transplant underwent transplantation much earlier at an average age of 17 months whereas the mean age for transplantation was 8.2 years.  The mean serum MMA dropped from 1648 μmol/L to 305 μmol/L (at four months post-Tx).  This level is still 1000-fold elevated but was low enough to eradicate episodes of hyperammonemia.  In addition, it was associated with stabilization of neurocognitive development.

The Connection Between Anxiety and Gastroesophageal Reflux Disease

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Why is it that reflux is so much worse during periods of anxiety and depression?

A recent prospective study (Kessing BF et al. Clin Gastroenterol Hepatol 2015; 13: 1089-1095) of 225 consecutive patients with symptoms of gastroesophageal reflux disease (GERD) looks into this issue.  All patients underwent ambulatory 24-hour pH-impedance (pH-MII) monitoring and had assessment of anxiety/depression with the Hospital Anxiety and Depression Scale.

GERD was defined by having pathologic acid exposure time and/or positive temporal correlation between the occurrence of symptoms ad reflux episodes. Hypersensitivity to reflux was considered if there was physiologic acid exposure times while having temporal association between reflux episodes and symptoms.  Functional heartburn indicated the presence of symptoms with a normal pH-MII.

Key findings:

  • 147 patients had GERD and 78 had functional heartburn; 36 patients were considered hypersensitive to gastroesophageal reflux.
  • Among patients with GERD (including patients with hypersensitivity), increased anxiety/depression levels were associated with more severe retrosternal pain/burning. However, anxiety/depression were NOT associated with an increased number of reflux episodes or number of symptoms reported on pH-MII.
  • Patients with functional heartburn had higher levels of anxiety than patients with GERD.

Bottomline: Anxiety is associated with increased GERD symptoms.  In addition, anxiety is more prevalent in patients with functional heartburn.

Briefly noted: Review (Lipa S, et al. Clin Gastroenterol Hepatol 2015; 13: 1058-67) of 4 trials with 153 analyzed patients:  “Stretta [radiofrequency ablation] for patient with GERD does not produce significant changes, compared with sham therapy, in physiologic parameters, including time spent at pH less than 4, LESP, ability to stop PPIs, or HRQOL.”.

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Cumberland Island

Cumberland Island

Complications with G-tube Placement

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Two recent studies highlight the risks with gastrostomy tube (G-tube) placement.

  • McSweeney ME, et al. J Pediatr 2015; 166: 1514-9.
  • Jacob A, et al. J Pediatr 2015; 166: 1526-8.

The first study, a chart review of 591 patients, identified a 10.5% major complication rate and ~25% complication rate overall.  By far the most common complication for both major and minor complications was stoma infections.  In this study, the g-tube used was the Corflo PEG tubes using a pull-procedure.  Perioperative antibiotics (i.e. cefazolin for 24 hrs) were administered. Exchange of g-tubes (to a skin-level device) took place at 6 months in most patients.  Major complications were defined as an unplanned adverse event necessitating additional hospitalization, surgery or interventional procedure.

Key findings:

  • Cumulative incidence of major complications was 2.4% within 48 hours, 5.8% with 1 month, 9.2% within 6 months, and 14.7% at 12 months post-G-tube placement
  • Among the 62 patients experiencing major complications, 55 of the 72 were due to infections, 6 were dehiscence of PEG at exchange, 2 were due to granulation needing surgery, 2 were due to colon perforation, and 1 due to pneumoperitoneum.  Other major complications included: 1 aborted PEG procedure, 1 post-PEG cardiopulmonary arrest, 3 malfunctioning PEG tubes, and 1 failure to exchange PEG tube for a skin-level device.

Overall, this study shows a fairly high rate of significant complications and that their occurrence was usually not in the immediate post-operative period.

The second study was a prospective study of 183 children undergoing a one-step percutaneous G-tube using the MIC-KEY introducer kit.  This one-step button requires insertion of three gastropexy anchors, dilatation of gastrostomy tract, and button measurement.  The authors evaluated the safety technique and the learning curve.

Key Findings:

  • In the first 6-month period, the authors noted a 17% failure rate; this declined to 0-7% in the following 6-month study periods.
  • The time for placement improved from 21 minutes during the first 6-months to 12 minutes during the sixth 6-month study period
  • The authors highlighted several advantages: 1. lower peristomal infection rate (10.6% compared to their historical control of 29% with pull-PEG); the PEG avoids need to bypass the oropharynx. 2. One procedure/anesthetic for a skin-level device.
  • In the article, the results indicate that there are clearly tradeoffs for these advantages: after the initial learning curve, their remained complications in the majority (65%), mostly mild complications which included accidental button removal (35%), gastric heterotopy (24%), and peristomal leakage (15%).  Also, 35% of patients returned for a replacement tube before the planned date because of intragastric balloon deflation.
  • The cost savings with this one-step button were estimated to be 11% lower.

Bottomline: While g-tubes remain important in caring for children with feeding problems, there is not a magic bullet to eliminate complications.  Understanding the frequency of these problems and discussing them with families will help them be addressed promptly.

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Resource:

www.feedingtubeawareness.com  This site contains a terrific PDF download which explains enteral tubes in an easy to understand style along with good graphics. “What You Need to Know Now, A Parent’s Introduction to Tube Feeding is the guidebook that every parent wished they had when they were first introduced to feeding tubes.”

How High Can You Go with Adalimumab?

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A recent study (Inflamm Bowel Dis 2015; 21: 1047-53) explored the “Efficacy and Safety of Adalimumab 80 mg Weekly in Luminal Crohn’s Disease.”

Methods: Between 2011-2012, 42 adults with active Crohn’s disease, defined by CDAI > 150 and an objective marker of inflammation, had a dose escalation of adalimumab to 80 mg weekly in prospective multi center study.

  • Objective markers could include CRP >0.5 mg/dL, fecal calprotectin >300 mcg/g, radiologic evidence or endoscopic evidence
  • Only 4 patients were receiving concomitant immunomodulators (& none were started)
  • There were no reports of adalimumab drug levels

Findings: At 14 weeks, 33.3% achieved a clinical remission (CDAI <150) and 23 (54.8%) had a clinical response.  These patients had associated improvements in CRP.  The authors do not report on serious adverse events; all AEs “were consistent with previous experience with this drug.”

Take-home point: The authors do not recommend this approach in routine clinical practice at this time.  However, it would seem that some patients with low adalimumab trough levels (and no anti-drug antibodies) may benefit from high doses of adalimumab

Briefly noted:

Fumery M, et al. JPGN 2015; 60: 744-48.  This retrospective study identified 27 children who received adalimumab (ADA) after infliximab failure.  Though ADA was well-tolerated, 8 (30%) had primary nonresponse to ADA and an additional 5 (26%) had ADA failure by 1 year.

Huang EY, et al. Inflamm Bowel Dis 2015; 21: 963-72.  “Exposure to dexamethasone in mice led to substantial shifts in gut microbiota over a 4-week period.” Take-home point: Corticosteroids may have both direct and indirect impacts on the microbiome as one mechanism of influencing disease response

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Zoo Atlanta

Zoo Atlanta