Guidelines for Esophageal Atresia-Tracheoesophageal Fistula

Posted on November 22, 2016 by gutsandgrowth

From a NASPGHAN-ESPGHAN working group of surgeons and pediatric gastroenterologists. a recent guideline (U Krishan et al JPGN 2016; 63: 550-70) regarding esophageal atresia (EA) and tracheoesophageal fistula (TEF) has made 36 specific statements and graded the evidence for these recommendations.

On GERD:

Low level evidence: The authors recommended starting PPIs in the neonatal period and continuing them “up to the first year of life or longer, depending on persistence of GERD.”
High level evidence: pH monitoring is useful in evaluating the severity of acid reflux in patients with EA. Low level evidence: pH-impedance monitoring is useful to evaluate and correlate non-acid reflux in selected patients.
High level evidence: “Endoscopy with biopsies is mandatory for routine monitoring of GERD in patients with EA.” The authors recommend evaluation (pH, impedance, and/or endoscopy) at time of stopping anti-acid treatment and during long-term follow-up. Specifically, with low level of evidence, the authors advocate for one endoscopy after stopping PPI therapy, one before age 10 years, and one at transition to adulthood.”
High level evidence: Fundoplication has accepted role, despite dysmotility, in patients with recurrent anastomotic strictures and poorly controlled GERD despite maximal PPI therapy. Full evaluation prior to fundoplication is recommended.

Other Statements:

Low level evidence: the authors recommend regular multidisciplinary evaluation, the authors note that symptoms of aspiration during swallowing may be identical to GERD symptoms, and evaluation of dysphagia with EGD/UGI.
High level evidence: ENT evaluation may disclose other anatomic abnormalities
Low level evidence: The authors recommend that anastomotic strictures be excluded in symptomatic children and that there is no “evidence that routine screening and dilatation” is necessary in asymptomatic patients.
Low level evidence: Management of EA patients with eosinophilic esophagitis (EoE) should follow the treatment of EoE in non-EA patients.
High level evidence: Incidence of Barrett’s esophagus is increased in adults with EA.
No level evidence: Potential treatments for recurrent strictures: steroids, mitomycin C, stents, and endoscopic knife.

While some these recommendations noted above are based on low level evidence, it is worthwhile for experts to provide their opinions. At the same time, there are some completely useless statements included in the guidelines, like those that suggest tailoring the treatment to the underlying problem. For example: “Statement 19: We recommend tailoring management of post-fundoplication dysphagia to the underlying mechanism(s).” Another useless statement: “Statement 21: No data are available on the most efficacious methods of avoiding feeding disorders in children with EA. However, the committee recommends a multidisciplinary approach to prevent and treat feeding difficulties.” (very low level evidence). In my view, shortening the number of recommendations, mainly by eliminating the useless ones, would have been helpful.

My take: Despite my view that about 20% of the recommendations are useless (Statements 17, 19, 21, 25, 26A & 26B, 31, and 34), the overall guideline is helpful and it is still worthwhile for experts to provide their recommendations.

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Good News from the Bad News Department: Outcomes of Intestinal Transplantation in Patients with Crohn’s Disease

Posted on November 20, 2016 by gutsandgrowth

Briefly noted: A recent retrospective study (BN Limketkai et al. Clin Gastroenterol Hepatol 2016; 14: 1574-81) examined outcomes of 142 patients with Crohn’s disease (CD) out of a total of 1115 cases of intestinal transplantation. The authors examined the Scientific Registry of Transplant Recipients. Since intestinal transplantation would be a very undesirable outcome in patients with CD, I titled this post as coming from the “Bad News Department.” The good news is that in the last 15 years, patients with CD disease do not appear to have worsened outcomes compared to patients without CD. Overall, during the period 1990-2014, the risk of graft failure was higher, mainly due to the initial 10 years. Graft failure was 18.6% at 1 year, 38.7% at 5 years, and 49.2% at 10 years in patients with CD compared with 14.1%, 32.1% and 41.0% in non-CD patients. The cumulative risk of death at 10 years for CD patients was 59.7%.

My take: It is good that intestinal transplantation outcomes for CD patients are now similar to all patients. In addition, intestinal transplantation outcomes are improving. Nevertheless, there is still a high death rate over 10 years.

Vedolizumab Study in IBD

Posted on November 16, 2016 by gutsandgrowth

From CGH Associated Editor Charles Kari:

Effectiveness and Safety of Vedolizumab Induction Therapy for Patients With Inflammatory Bowel Disease

Vedolizumab is a biologic agent which targets the integrin receptor and is approved for the treatment of patients with moderate-severe ulcerative colitis (UC) and Crohn’s disease (CD). Vedolizumab inhibits the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM–1).

In this [November] issue of Clinical Gastroenterology and Hepatology, Amiot and colleagues report the effectiveness and safety of vedolizumab induction therapy in patients with moderate-to-severe active UC and CD who previously failed anti-TNF therapy. Active IBD was defined according to the Harvey-Bradshaw index (HBI) >4 for CD patients and the Mayo Clinic score ≥6 for UC patients. Patients received intravenous vedolizumab at a dose of 300 mg at weeks 0, 2 and 6 and then every 8 weeks through week 52. Concomitant use of corticosteroids, immunomodulators, or methotrexate was permitted. The primary outcome measure was steroid-free clinical remission at week 14, which was defined as a HBI ≤4 for CD patients and a partial Mayo Clinic score ❤ with a combined stool frequency and rectal bleeding subscore of ≤1 for UC patients. A total of 294 patients were enrolled (CD, 173; UC, 121), of whom 276 completed the induction period. At week 14, 63 (36%) and 47 (39%) patients were in clinical remission in the CD and UC groups, respectively, of whom 53 (31%) and 43 (36%), respectively, were in steroid-free clinical remission. The clinical response rates at 14 weeks were 64% for CD patients and 57% for UC patients. Adverse events occurred in 93 patients (31.6%) out of 294 patients with serious adverse events in 24 (8.2%) and adverse events leading to vedolizumab discontinuation in 15 (5.1%) including one case of pulmonary tuberculosis.

In conclusion, in a cohort of IBD patients who failed anti-TNF therapy and received vedolizumab, about one third experienced steroid-free clinical remission at 14 weeks, with good safety profile (Figure 3).

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Safer Than You Think: Biologic Therapies for IBD and Risk of Infection and Malignancy

Posted on November 14, 2016 by gutsandgrowth

While there have been a number of studies which have highlighted the potential risks of biologic agents, many studies have NOT identified any risk of infection or malignancy.

Another recent systematic review/meta-analysis (S Bonovas et al. Clin Gastroenterol Hepatol 2016; 14: 1385-97) provides reassuring data regarding the following biologics: infliximab, adalimumab, certolizumab, golimumab, natalizumab, and vedolizumab.

The authors identified 49 randomized placebo-controlled studies with 14,590 participants.

Key findings:

There was a moderate infection risk with odds ratio of 1.19 (19% increase in odds of developing an infection) and significant increase in opportunistic infections (eg. tuberculosis) OR 1.90
Risk of serious infections was NOT increased in patients treated with biologics with OR 0.89. In studies with low risk of bias, the risk of serious infections had OR of 0.56.
No increase in malignancy risk was identified with OR 0.90 but the authors note that data was insufficient in terms of exposure and follow-up to be conclusive.

The authors note that the studies including in this review challenge some of the findings of observational studies. “However, observational studies lack the experimental random allocation of participants…the discrepancies between observational studies and randomized trial evidence might be explained by the inability of observational designs to fully address the complex and important differences between the IBD patients receiving and those not receiving biologics.”

Study limitations include “sponsorship bias -because the trials were supported by pharmaceutical companies and limited followup of 24 months. In addition, most of the trials in the meta-analysis were judged to be at high or unclear risk of bias because of their methodological characteristics.

My take: This study indicates that biologic therapies do not appear to increase the risk of serious infections and may not increase the overall risk of malignancy.

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Salivary Pepsin Doesn’t Pass Muster for Evaluation of Reflux

Posted on November 7, 2016 by gutsandgrowth

For quite a long time, I thought the expression was “Pass Mustard”.

A recent study (F Dy et al. J Pediatr 2016; 177: 53-8) shows that testing salivary pepsin is probably a waste of time in assessing for extraesophageal reflux disease. The authors prospectively recruited 50 children who underwent multiple studies including 24-hour pH-MII testing. The idea of pepsin as a biomarker has some plausibility since it is produced in the stomach and its presence in the oropharynx (or airway) would be unexpected. Since salivary pepsin does not require invasive diagnostic testing, it would be useful if it had adequate sensitivity and specificity.

Key findings:

21 of 50 (42%) were salivary pepsin-positive with a median concentration of 10 ng/mL. Pepsin was detected in 6 of 21 with abnormal impedance testing and 8 of 21 with abnormal pH results (per Table 1 –the discussion used a denominator of 11 for each of these results)
There was no significant correlation between salivary pepsin-positivity compared with salivary pepsin-negative for reflux episodes, acid reflux, nonacid reflux or any other reflux variable.
The authors also reiterate in the discussion that clinical trials, evaluating reflux and chronic cough, “have failed to find a consistent relationship between measure dreflux and clinical response.”
The authors note that bronchoscopy pepsin correlation with esophageal reflux monitoring was similarly low in sensitivity
The authors note that “one-third of healthy asymptomatic adults have pepsin detected in their saliva.” In this study, 38% (15 of 39) of children had pepsin detected despite normal impedance results.

My take: While this study mainly shows that pepsin detected in the saliva has no practical use in correlation with reflux, the bigger picture is the uncertain relationship of reflux as a causal association with chronic cough.

Any of the reflux-esophageal gurus care to comment?

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What Happens When Infliximab Is Stopped in Patients with Ulcerative Colitis Remission

Posted on November 4, 2016 by gutsandgrowth

‘If it ain’t broke, don’t fix it’

Perhaps, the above sentiment is needed for patients with ulcerative colitis who are doing well with infliximab therapy according to a recent study (G Fiorino et al. Clin Gastroenterol Hepatol 2016; 14: 1426-32).

In this multicenter retrospective cohort study, 111 patients with ulcerative colitis who had been in remission (>12 months) were followed after stopping infliximab (IFX) and compared with 82 controls who remained on therapy. Here’s what happened (see Figure 1 in study):

Among those who discontinued IFX, 53 patients (47.7%) relapsed in the followup period. This corresponded to an incidence of 23.3 per 100 person-years and with a median time to relapse of 3.6 years.
In comparison, for those who remained on IFX, 14 relapses (17.1%) occurred which corresponded to an incidence of 7.2 per 100 person-years at risk and with a median time to relapse of 7.6 years.
Thiopurine use after stopping IFX seemed to diminish the risk of relapse: 15.0 per 100 person-years compared with 31.2 per 100 person-years for those taking an aminosalicylate alone.
For those who restarted IFX, 77.1% had a response and 51.4% returned to remission; however, 17.1% had infusion reactions.

My take: In a real-life experience, stopping IFX in patients with ulcerative colitis who had been in sustained clinical remission resulted in a higher relapse rate. This finding is consistent with other studies.

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Advice on Abdominal Pain for Everyone Who Cares for Children

Posted on November 3, 2016 by gutsandgrowth

A recent editorial (MK Farrell. J Pediatr 2016; 177: 16-17) provides many useful pointers from a master clinician along with commentary on an epidemiology study of recurrent abdominal pain (ML Lewis et al. J Pediatr 2016; 177: 39-43).

The main finding of the study which used an internet survey of mothers (children 4-18) was that 23% of US children met the Rome III criteria for a functional GI disorder. Constipation was the most common.

Key points in commentary:

John Apley’s monograph The Child with Abdominal Pains “should be read by all who care for children.”
Worldwide prevalence of functional GI disorders has been estimated to be 13%. Peak ages were 4-6 years and early adolescence with a greater prevalence in females
“A variety of phamacologic and nonpharmacologic treatments have been proposed, but none have been consistently effective except perhaps cognitive behavioral therapy and hypnotherapy.”
“Negative studies are not reassuring” [to families]

Pithy observations from Apley:

“The more time the doctor spends on the history, the less time he is likely to spend on treatment.”
“Doctors who treat the symptoms tend to file a prescription. Doctors who treat the patient are more likely to offer guidance.”
“It is a fallacy that a physical symptoms always has a physical cause and needs a physical treatment.”
“Anxiety like courage is contagious.”

My take: Dr. Farrell urges more research focus on interventions (diet, behavioral, alternative therapies, medical treatments) to improve outcomes and less focus on epidemiology.

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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.

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Changes in the Use of IBD Biologic Therapy

Posted on November 1, 2016 by gutsandgrowth

A recent study (W-J Lee et al. Inflamm Bowel Dis 2016; 22: 2410-17) offers a great deal of insight into changes in the use anti-Tumor Necrosis Factor Alpha (ant-TNF) therapy from 2009-2013 in patients ≤24 years. The authors utilized databases with about 180 million people and identified 11,962 patients with inflammatory bowel disease (IBD).

Key findings:

3300 of the 11,962 (27.6%) patients were treated with anti-TNF therapy.
Top-down treatment: 1298 of 3300 (39.3%) were treated with top-down therapy which was defined as usage of anti-TNF therapy within 30 days of first IBD medication prescription. Interestingly, over the course of the study, there was a trend towards more top-down (versus step-up) therapy and shorter time to initiation of anti-TNF therapy. In 2009, 31.4% used a top-down approach compared with 49.8% in 2013.
Top-down therapy is associated with lower rates of corticosteroid use.
Infliximab dominant anti-TNF: infliximab was the anti-TNF in 89.2% of patients less than 12, 82.3% of patients 12-17, and 55.1% of patients 18-24. Adalimumab accounted for the vast majority of the other TNF users. Though, the authors note a trend towards increasing use of adalimumab in both adult and pediatric patients in a separate study (Park KT et al. Inflamm Bowel Dis 2014; 20: 1242-49)
Cotherapy: thiopurines and methotrexate were used as cotherapy in 13.5% and 7.2% of top-down group compared with 54.8% and 14.6% respectively in step-up strategy.
Drug therapy among non-TNF users: 25.4% (2199) received a thiopurine, 79.3% (6871) received a 5-aminosalicylate, and 2.3% (201) received methotrexate.
Anti-TNF therapy discontinuation: Using top-down strategy 69.2% persisted on infliximab at 12 months and 56.8% persisted at 24 months. In comparison, using step-up approach with infliximab, it was 72.7% at 12 months and 64.0% at 24 months. The numbers were quite similar with all the anti-TNF agents indicating that step-up approach had significantly lower rate of anti-TNF discontinuation. The authors speculate that one factor could be use of cotherapy or possibly other adverse reactions.

The authors explain some of the limitations of their study in its reliance on databases, particularly with regard to misclassification. However, in my opinion, these limitations do not affect any of the trends that the authors are able to document.

My take: For most of my patients, I have preferred to continue to utilize cotherapy and/or step-up therapy because I think there is likely to be a more durable anti-TNF response. The fairly small differences in anti-TNF durability have huge implications for those who lose anti-TNF responsiveness given the limited treatment options.

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GI Educational Cartoons For Children

Posted on October 29, 2016 by gutsandgrowth

Diana Lerner and the Medical College of Wisconsin have developed additional GI educational videos. Previously, they had developed cartoon videos explaining endoscopy (prev post: Terrific Educational Videos on Endoscopy). Now there are several more. All of these are in English and some in Spanish.

Topics include inflammatory bowel disease, gastroesophageal reflux, eosinophilic esophagitis, and celiac disease.

Here’s the link: Pediatric Gastroenterology Cartoons For Kids

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October 2016: IBD Studies

Posted on October 28, 2016 by gutsandgrowth

Briefly noted:

E Zittan et al. Inflamm Bowel Dis 2016; 22: 2442-47. In this study with 773 patients with history of ulcerative colitis/ileal pouch-anal anastomosis, there was no significant difference in complications/leak among the 196 with preoperative anti-TNF exposure (n=26, 13.2%) compared with the control group (n=66, 11.7%). Preoperative anti-TNF exposure does not appear to worsen outcomes after surgery.

C Hartman et al. JPGN 2016; 63: 437-444. This cross-sectional survey of 68 children with IBD (57 Crohn’s disease) found frequent nutrient deficiencies based on 3 day diet records. Interestingly, children on exclusive enteral nutrition were much less likely to have inadequate intakes of energy, minerals, or micronutrients. This article provides plenty of reasons for children with IBD, particularly Crohn’s disease, to work with a nutritionist.

M Fischer et al. Inflamm Bowel Dis; 2016; 22: 2402-09. In a cohort study of 67 patients (35 with Crohn’s, 31 with ulcerative colitis, and 1 indeterminate colitis), fecal microbiota transplantation (FMT) for refractory Clostridium difficile infection was successful in 53 (79%) with a single infusion. Four of the 14 failures, subsequently responded to anti-CDI antibiotics. Of the 8 who had a 2nd FMT, 6 were successful; and 1 of 2 responded to 3rd FMT. Thus, 60 of 67 responded overall to FMT. After FMT, IBD disease activity was reported as improved in 25 (37%), no change in 20 (30%) and worse in 9 (13%). In this cohort, 1 needed colectomy and 1 needed diversion. This article indicates that FMT for CDI in IBD was associated with high cure rates and low risk of IBD flare.

A Khoruts et al. Clin Gastroenterol Hepatol 2016; 14: 1433-38. This was a study of 272 consecutive patients that underwent FMT for recurrent CDI. 15% had established IBD and 2.6% were determined to have IBD at time of FMT. 74.4% of IBD patients responded to a single FMT compared with 92.1% of patients without IBD. More than one quarter of IBD patients experienced a clinical flare after FMT.

MA Conrad et al. Inflamm Bowel Dis; 2016: 22: 2425-31. This review of early pediatric experience with vedolizumab in 21 subjects (16 with Crohn’s disease) identified a clinical response in 6/19 (31.6%) evaluable subjects at week 6 and 11/19 (57.9%) by week 22. Steroid-free remission was noted in 3/20 at 14 weeks (15%) and 4/20 (20.0%) at 22 weeks. Overall, this shows a fairly low response rate to vedolizumab in this highly selected cohort. Prospective pediatric studies of vedolizumab are needed to identify which patients are most likely to benefit.

University of Virginia Rotunda