Category Archives: Pediatric Gastroenterology Intestinal Disorder

FMT -not quite the new Laser

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I distinctly remember one of my high school teachers saying that if you asked someone if they were willing to have a serious operation like a brain lobe removal, that most would be unwilling unless there was no other choice.  However, if you told them that you were going to do it with a laser, people would want to get it done right away.  Such was the mesmerizing appeal of the word “laser.”

Fecal microbiota transfer (FMT) certainly does not sound as enticing as a laser treatment. Nevertheless, the authors of a recent report state that “we received interest from patients all over the world to participate.”  That being said, this recent report reintroduces the concept of FMT for ulcerative colitis (UC) (JPGN 2013; 56: 597-601).

In the introduction, the authors note that probiotics, in particular VSL#3, have shown usefulness in the treatment of UC and have noted previous sporadic reports of FMT for inflammatory bowel disease.  This led to their pilot study of 10 subjects (7 to 21 years); this was a single-center, uncontrolled study.  Due to financial constraints, there was no correlation with fecal microbial profiling, histologic/colonoscopic activity, or stool inflammatory markers.

The authors extensively describe their protocol of FMT (240 mL [in four aliquots] daily for five days) including donor exclusion criteria and donor screening.  Participants did not receive any bowel preparation prior to FMT.  The majority of participants had pancolitis;  only one patient had disease limited to proctitis. One of the ten patients could not retain FMT enemas.

Results:

  • Short-term improvement was noted with 7 of 9 (78%) achieving a clinical response within one week and 3 of 9 (33%) achieving a clinical remission.
  • The authors note that 6 of 9 (67%) maintained a clinical response at 1 month.  Although if one examines the study’s figure 2, this graphically demonstrates a fairly meager response in about half of these patients based on their PUCAI score.
  • The authors do not overstate their interpretation of their results.  “This unique biologic is potentially efficacious.”
  • Adverse effects appeared to be mild and self-limiting.

Ultimately if FMT proves efficacious for inflammatory bowel disease, feces with the right microbial mix would be quite valuable.  For now, this study indicates that further research is needed in this area.

Related blog entries:

What really causes Celiac disease?

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A fascinating article in the NY Times delves into a number of environmental factors that are likely playing a role in the increasing incidence of celiac disease. Here’s the link (thanks to Kayla Lewis for this reference):

Some excerpts:
“Scientists are pursuing some intriguing possibilities. One is that breast-feeding may protect against the disease. Another is that we have neglected the teeming ecosystem of microbes in the gut — bacteria that may determine whether the immune system treats gluten as food or as a deadly invader.Celiac disease is generally considered an autoimmune disorder. The name celiac derives from the Greek word for “hollow,” as in bowels. Gluten proteins in wheat, barley and rye prompt the body to turn on itself and attack the small intestine. Complications range from diarrhea and anemia to osteoporosis and, in extreme cases, lymphoma. Some important exceptions notwithstanding, the prevalence of celiac disease is estimated to range between 0.6 and 1 percent of the world’s population….Yet the more scientists study celiac disease, the more some crucial component appears in need of identification. Roughly 30 percent of people with European ancestry carry predisposing genes, for example. Yet more than 95 percent of the carriers tolerate gluten just fine. So while these genes (plus gluten) are necessary to produce the disease, they’re evidently insufficient to cause it….

A recent study, which analyzed blood serum from more than 3,500 Americans who were followed since 1974, suggested that such a trigger could strike adults at any time. By 1989, the prevalence of celiac disease in this cohort had doubled.

“You’re talking about an autoimmune disease in which we thought we had all the dots connected,” says Alessio Fasano, head of the Center for Celiac Research and Treatment at the Massachusetts General Hospital for Children in Boston, and the senior author of the study. “Then we start to accumulate evidence that there was something else.”

Identifying that “something else” has gained some urgency. In the United States, improved diagnosis doesn’t seem to explain the rising prevalence. Scientists use the presence of certain self-directed antibodies to predict celiac disease. They have analyzed serum stored since the mid-20th century and compared it to serum from Americans today. Today’s serum is more than four times as likely to carry those antibodies…

your microbes change you, but your genes also shape your microbes — as do environment, breast milk, diet and antibiotics, among many other factors.

Such complexity both confounds notions of one-way causality and suggests different paths to the same disease. “You have the same endpoint,” Dr. Jabri says, “but how you get there may be variable.”…

In a far-flung corner of Europe, people develop celiac disease and other autoimmune diseases as infrequently as Americans and Finns did a half-century ago. The same genes exposed to the same quantity of gluten do not, in that environment, produce the same frequency of disease.

“We could probably prevent celiac disease if we just give the same environment to the Finnish children as they have in Karelia,” says Dr. Hyoty. “But there’s no way to do it now, except to move the babies there.”

Author of NY Times article:

Moises Velasquez-Manoff.  Also, he is the author of “An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases.”

Related blog links:

Celiac disease and less diabetes?

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While there is a well-recognized association between Celiac disease and insulin-dependent diabetes mellitus (IDDM), a recent study shows a lower prevalence of non-insulin dependent diabetes mellitus (NIDDM) and metabolic syndrome in patients with celiac disease (Gastroenterol 2013; 144: 912-17).

You-Tube Link: Patients With Celiac Disease Have a Lower Prevalence … – YouTube..Dr. Toufic A. Kabbani discusses his manuscript “Patients WithCeliac Disease Have a Lower Prevalence of Non-Insulin-Dependent Diabetes Mellitus and Metabolic Syndrome.”

A retrospective review of 840 patients with biopsy-confirmed celiac disease were compared with 840 random matched controls.  Controls were matched for age, sex, and ethnicity.  Mean age was 49.4 years.

Key findings:

  • 26 (3.1%) of celiac disease cohort and 81 (9.6%) (p <0.0001) had NIDDM.
  • 3.5% of celiac disease cohort and 12.7% of controls had metabolic syndrome.
  • Though celiac disease patients had lower BMI, these findings were still present after controlling for this variable.
  • Prevalence of NIDDM was strongly associated with age in both groups.  In celiac cohort, NIDDM occurred in 0% (n=343) of those <45, 3.1% in 45-64, and 9.3% in those >65.  In contrast, the control group had NIDDM in 3.5%, 11% and 19.3% respectively.

With regard to pathophysiology, the authors did not think the protection from NIDDM was related to malabsorption.  Evidence of malabsorption was more common in patients with CD and NIDDM than in those without NIDDM.

Related blog posts:

 

PPI Side Effects: “Dissecting the Evidence”

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While proton pump inhibitors (PPIs) are used extensively for acid-related diseases and have been around for nearly 25 years, there have been a number of reports about potential side effects.  As a drug class, PPIs have a very good safety profile.  A recent article reviews some controversial adverse effects and summarizes the evidence for and against (Clin Gastroenterol Hepatol 2013; 11: 458-64).

I. Calcium/bone effects.  After reviewing a number of studies, the authors conclude: “There is no good evidence to establish that PPI use has a significant risk for bone density loss or osteroporotic-related fractures….Supplemental calcium is not recommended or justified solely because of PPI use.”

II. Iron. “Although it is conceivable that PPI therapy may reduce absorption of nonheme iron and retard iron pool replenishment, this effect has not been well-studied or evident from widespread use in clinical practice.

III.  Magnesium.  “The FDA recommendation to consider checking magnesium levels before starting is not practical, in particular for the over-the-counter market. In patients who may be predisposed to …ongoing magnesium loss…it may be reasonable to follow…Given the rarity of the reports and no controlled studies to delineate the mechanisms, it is important for health care providers to be aware of this” (rare reports of profound hypomagnesemia).

IV. Pneumonia. “Small relative risk associated with short-term and high-dose PPI use.  These relationships, however, do not offer a definitive explanation for the relative risk” due to the studies and confounding factors.

V. Clostridium difficile.  “To date, there is insufficient evidence to conclude that there is a definitive relationship between PPI use and C difficile infection…clinicians should be aware of this potential relationship.”

VI. Traveler’s diarrhea.  “The data…were overall supportive of no associated risk, albeit there were a few specific case reports suggesting a remote causal association.”

VII. Small intestinal bacterial overgrowth. “The relationship between PPI use and the development of SIBO is still not understood.”

VIII. Interstitial nephritis.  Extremely rare. “Investigators…did not find enough evidence to support a causative relationship.”

IX. Methotrexate.  “Coadministration of PPIs with high-dose methotrexate appears to be correlated with delayed methotrexate elimination.”

Also discussed: Vitamin B12, Clopidogrel, Spontaneous bacterial peritonitis

The authors conclude that the above reported associations have received considerable attention.  “Because PPIs are overprescribed in many patients, …the clinical effects always should be reviewed and attempts should be justified to stop any therapy that may not be needed.”

Related blog entries:

Tacrolimus for Refractory Crohn’s Disease

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While tacrolimus has been considered a potential option for refractory Crohn’s, data on its usage are sparse, mostly small retrospective studies.  Another small retrospective study from the Mayo clinic provides data from their experience with 24 adult patients who were treated with tacrolimus for a median of 4 months (Inflamm Bowel Dis 2013; 19: 1107-11).

17 (71%) of study participants were female and their median age was 38 years.  18 (75%) had ileocolonic disease.  All patients were either intolerant or unresponsive to at least one anti-TNFα agent.  Most patients received concurrent therapy: thiopurines (58%), methotrexate (8%) and antibiotics (46%).

Results:

  • 67% responded to tacrolimus and 21% achieved a steroid-free remission.
  • Patients with trough levels of 10 to 15 ng/mL had the highest response (86%) and remission (57%).
  • Adverse events were common (75% of patients); 8 (33%) required dose reduction and 6 (25%) led to treatment discontinuation.  Frequent adverse events included acute kidney injury (29%), paresthesia (29%), headache (17%), and tremor (17%).
  • 54% of patients in this series required surgery within a median of 10 months after starting tacrolimus.
  • Of the patients who achieved remission (n=5), 2 were transitioned to immunomodulator therapy to minimize long-term toxicity. 1 patient did well after stopping all therapy during a 6 month followup.  1 patient stopped treatment due to paresthesias and 1 patient continued therapy for 2.5 years.

The study does not describe the use of antibiotics for the prevention of Pneumocystis jiroveci pneumonia.

Take-home message: Tacrolimus doesn’t look too promising for refractory disease.

Related blog post:

Additional references:

  • -IBD 2008; 14: 7-12. Tacrolimus of minimal efficacy for UC and Crohn’s. Some achieve response (22/32 in UC and 7/15 in Crohn’s) only 3/32 UC with remission and 1/15 Crohn’s with remission
  • -Gut 2006; 55: 1255-1262. Use of prograf in refractory UC. Troughs 10-15, then 5-10 after remission; partial response in 68% at week 2 & 58% at week 10 (n=19)
  • -Gastroenterol 2003; 125: 380. Tacrolimus helped but did not cure fistulizing disease
  • -J Pediatr 2000; 137: 794-799. n=14.
  • -Am J Gastro 1997; 92: 876. Use in fistualizing Crohn’s.
  • -Am J Gastro 1998; 93: 18. Use in IBD.
  • -IBD 1999; 5: 239. Combined c azathioprine for perianal fistulae. response: initial 2.4weeks, 12.2weeks complete. 7/11 c complete response.
  • -IBD 2009; 15: 193. topical tacrolimus for proctitis. 10/12 w proctitis responded to 2 mg or 4 mg enema in 100 mL of sterile water.
  • -IBD 2007; 13: 245. Use for perianal disease.
  • -Gut 2000; 47: 436-440. Topical tacrolimus may be effective in the treatment of oral and perineal Crohn’s disease.

Breaking down lung defenses in Cystic Fibrosis

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Cystic fibrosis patients develop chronic neutrophilic inflammation of the airways.  Neutrophils which help fight off bacterial infections also release peroxidases and proteases which can damage the lung tissues.  Neutrophil elastase which is one of the proteases elaborated by neutrophils can digest elastin; this is prevented by α-1-antitrypsin.  However, when there is excessive free neutrophil elastase this can overwhelm this protection.  A recent study has shown that neutrophil elastase activity in bronchoalveolar lavage (BAL) at 3 months of age was associated with early bronchiectasis (NEJM 2013; 368: 1963-70).

Design: 127 consecutive infants (from region of Western Australia) who were diagnosed with cystic fibrosis after newborn screening were recruited; however, 10 were too young and 3 were lost to followup due to relocation.  Most were followed for 3 years; 78 remained in the study at 36 months. Chest CT scans and BAL were performed at 3 months, 1 year, 2 years, and 3 years when patients were in stable clinical condition.

Bronchiectasis was identified by CT scan findings: “defined as a bronchus-to-artery ratio of more than 1.0 or the presence of a non tapering bronchus in the transverse plane.”

Key findings:

  • Point prevalence of bronchiectasis: 29.3% at 3 months, 31.5% at 1 year, 44.0% at 2 years and 61.5% at 3 years.
  • Free (unbound) neutrophil elastase activity in BAL fluid was a risk factor for bronchiectasis with an odds ratio of 3.02.  At 3 months of age, 23.3% had detectable neutrophil elastase activity in BAL fluid.
  • Other risk factors for bronchiectasis included meconium ileum (OR 3.17), and respiratory symptoms at time of CT (OR 2.27).

Take-home message: Damage happens to the lungs early in life. The related editorial (pg 2026) states “early cystic fibrosis lung disease is not ‘silent’ if you listen carefully.” To improve long-term outcome, early intervention will be necessary.

Related blog posts:

Natural History of EoE -Journal Club (Part 3)

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This posting reviews the final article for our eosinophilic esophagitis (EoE) journal club: Aliment Pharmacol Ther 2013; 37: 114-21.

Design: Cross-sectional study of adult EoE patients (≥ 18 years) who were diagnosed at the Children’s Hospital of Philadelphia.  Patients underwent dysphagia questionnaire, Mayo Dysphagia Questionnaire (MDQ-30), and a patient assessment of upper gastrointestinal disorders quality of life questionnaire (PAGI-QOL). Of 140 eligible patients, 53 completed the questionnaires, 66 were unable to be contacted, and 21 refused to participate.

The MDQ-30 has been validated as a tool for esophageal strictures of 15 mm or smaller.  It has not been confirmed as a EoE dysphagia tool.

Diagnosis: According to the authors, a diagnosis of EoE required a >20 eosinohils/hpf after a 2-month therapeutic trial of proton pump inhibitors.

Results:

  • Mean age 20.5 years.  98% were caucasian and 75% were male.  15% had a history of esophageal dilatation.
  • 6/53 had positive dysphagia scores.  However, 18/47 with negative scores reported ongoing difficulty swallowing.
  • 26 (49.1%) of subjects were receiving proton pump inhibitor therapy and 40 (76%) were following allergy-directed dietary elimination.  Most common allergy in this cohort was dairy (49%) followed by peanuts/tree nuts (23%), eggs (9%), wheat (9%), soy (8%), and seafood (2%).**
  • Overall, dietary QOL scores, but not overall QOL scores, were adversely affected by ongoing EoE.

**With regard to dietary therapy, there is a significant discrepancy in reported allergy avoidance in this cohort compared with some previous data published by this center. For example, Liacouras et al (Clin Gastro Hepatol 2006; 3: 1198) reported a  98% improvement with diet treatment (n=351) (2/3rds were treated with elemental diet, mostly NG, with food reintroduction).  Their protocol included rebiopsy after introduction of last new food.  75/242 responded to elimination of specific foods.  Overall pattern of food avoidance after biopsy: milk 45%, eggs 45%, soy 38%, corn 38%, wheat 30%, beef 30%, chicken 20%, potato /oats/peanuts 15%, turkey/barley 11%, pork 8%, rice 5%, green beans 3%, apples /pineapple 1%.*  The reported allergens in this study match up much more closely to a highly-selected group of patients that was more recently reported from their database and is reviewed separately (Picking the right diet for EoE | gutsandgrowth).  In this group, the authors stated that the most common foods by biopsy were the following: milk (35%), egg (13%), wheat (12%), soy (9%), corn (6%).

Study limitations:

  1. Small number of patients
  2. Low response rate/responder bias
  3. Retrospective cross-sectional study -does not provide longitudinal data
  4. Young age of subjects
  5. MDQ-30 not validated for dysphagia in EoE
  6. Tertiary children’s hospital with research focus on EoE
  7. No recent endoscopies in research cohort

Take-home message: EoE is a chronic disease with “little resolution of either symptoms or oesophageal eosinophilia without ongoing treatment.”

 

EoE -Journal Club (Part 2)

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The third article for our journal club: Aliment Pharmacol Ther 2013; 37: 1157-64.

This study involved a literature search which identified 10 articles which described the impact of proton pump inhibitor therapy for suspected eosinophilic esophagitis.  In total, these articles describe 258 patients (152 children and 106 adults).  Five of the studies were retrospective series.  The others included two randomized controlled trials, one randomized noncontrolled trial, and two prospective series.

Results: after PPI treatment, a clinical response was noted in 69% overall and histologic remission was evident in a mean of 44%.  Histologic remission was lower in children (23%-40%).  In two adult studies, both randomized controlled trials, PPI therapy (esomeprazole 40 mg/day) outperformed topical steroids (fluticasone 440 mcg bid); histologic remission was seen in 33% with PPI in both trials compared with 15% and 19% with fluticasone.

Key points in discussion:

  • PPI trial “is mandatory not only to confirm the presence of EoE, but to evaluate for PPI responsiveness.”  Yet, in surveys, …”only one-third of physicians thought it is necessary to initiate a PPI trial before diagnosing EoE.”
  • No clinical, endoscopic, histologic features nor pH testing “have demonstrated capacity to predict response to PPI therapy.”
  • PPI-REE “occurs in at least one-third of patients with suspected EoE, with response rates lower in children.”  Adults may have a higher response due to coexisting gastroesophageal reflux disease.

Related blog entry: gutsandgrowth | Pediatric Gastroenterology

EoE -Journal Club (Part 1)

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This week our Eosinophilic Esophagitis (EoE) journal club is meeting.  The first article had previously been reviewed on this blog: SFED works for EoE! | gutsandgrowth.

The second article examines the “Effect of Proton Pump Inhibitor on Esophageal Eosinophilia” (JPGN 2013; 56: 166-72). PPI responsive esophageal eosinophilia (PPI-REE) has also been discussed previously on this blog (EoE: Drugs, Diets, Dilatation and PPI–REE | gutsandgrowth); this article adds additional information to this subject and highlights the possibility of transient PPI-REE.

Design: retrospective review of 204 children with EoE (criteria included ≥15 dos/hpf) over an 11 year time span.  Only 35 subjects met the criteria of having an endoscopy before and after an exclusive 8-week trial of PPI (1-2 mg/kg/day).

Results: 8 of 35 subjects had clinical response and 7 had biopsy-confirmed response to PPIs ( 23%).  In five patients with durable response, mean eosinophil count decreased from 92 to 5 eos/hpf.  In addition, eosinophil peroxidase index (EPX) declined from 39.2 to 14.6.  Two patients experienced relapse despite initial PPI-responsiveness.  Clinical and histologic relapse occurred at 17 and 23 months respectively.  However, of the 5 subjects who did not experience relapse, average followup reported in study was only 8 months.

Study limitations: small number of patients, limited geographical area, tertiary medical center study, retrospective study, uncertain compliance with therapy, and variable dosing of PPIs

Take-home points:

  • No clinicopathologic features distinguished patients with PPI-REE from EoE patients or patients with transient PPI-REE. Yet, 23% (8/35) of initial cohort showed resolution of symptoms and 7/35 had resolution of esophageal inflammation after PPI treatment.
  • Potential explanations for transient PPI-REE: lack of PPI adherence, missed detection of EoE after PPI trial (patchy disease), variation in allergenic exposure, diminished effect of PPIs over time, fluctuation in EoE disease course unrelated to PPI usage

Related blog entries:

Also, for those of you who read all the way to the bottom, here’s a link to a culturally significant (aka viral video) advertisement that I thought was amusing (potty humor):

Kmart Big Gas Savings Ad (Video) – Daily Picks and Flicks

Anxiety and Functional Abdominal Pain

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A recent review highlights the importance of anxiety and functional abdominal pain (FAP) (JPGN 2013; 56: 469-74).

“Preliminary evidence suggests that anxiety frequently co-occurs with FAP.  This is not to suggest that FAP is a manifestation of a psychological disorder, but rather that anxiety and FAP may frequently co-occur because of potentially shared etiological factors (eg. heightened physiological arousal) or as a consequence of coping with recurrent pain.”

“Anxiety disorders are estimated to affect 42-85% of youth with FAP.”

Proposed guidelines for assessment and treatment of youth with FAP and anxiety:

Initial evaluation: build rapport between family and medical provider, assess for red flags, perform standard testing, anticipate and predict normal testing results, validate the pain experience is real, educate regarding pain sensation via brain-gut axis, administer anxiety screener (see below)

Management: reassure family that FAP is not a failure to identify an organic condition, avoid extensive testing, consider a low-dose antidepressant when appropriate

Psychosocial: if elevated levels of anxiety, refer for assessment by a psychologist, educate families about cognitive-behavioral treatment

With regard to screening, the authors propose the Screen for Child Anxiety and Related Disorders (SCARED) tool.  From the University of Pittsburgh website,

http://www.psychiatry.pitt.edu/sites/default/files/Documents/assessments/SCARED%20Child.pdf:

  • Target Population: Children ages 8-18 years
  • Intended Users: Clinicians and psychiatrists
  • Time to Administer: 10 minutes
  • Completed By: Children and parents
  • Modalities Available: Handwritten
  • Scoring Information: Severity of symptoms for the past three months is rated using a 0 to 2-point rating scale with 0 meaning not true or hardly ever true, 1 meaning sometimes true, and 2 meaning true or often true.

Many other subspecialists joke about the need for a psychiatry degree to be an effective pediatric gastroenterologist; this review suggests that they are not far off the mark.

Take-home message: the review covers important aspects of this ubiquitous problem.  Trying to get patients (and their parents) to address anxiety will likely improve outcomes of children with FAP.

Related blog links:

Additional references:

  • -JPGN 2011; 53: 200. n=98. 79% of FAP responded to low dose tricyclics
  • -Gastroenterol 2009; 137: 1261, 1207– Editorial. Amitriptyline helped in 66% vs 58% w placebo. n=90. dose 10mg <35kg, 20mg >35kg. 89% had failed Rx prior to study. ‘inability to use placebo.. in practice may justify amitriptyline Rx. Consider hypnotherapy/CBT first.’
  • Distraction/ignoring important: Pain 2006; 122: 43-52. (Walker LS et al), J Pain 2006; 7: 319-26.
  • -J Peds 2009; 154: 313 (editorial), 322. Prospective school study. n=237. Weekly prevalence of abd pain was 38%. 18% with persistence for >12 weeks. FAP persists into adulthood in 1/3 to 1/2 of cases (Clin Gastro Hepatol 2008; 6: 329-32).
  • -Acta Paediatr 2007; 96: 697-701. Maternal anxiety is most consistent predictor of outcome.