FMT -fecal microbiota transplant

An excellent review of FMT, especially in regard to C difficile infection, has been published (Am J Gastroenterol 2013; 108: 177-85)  Thanks to Ben Gold for sharing this reference.

FMT has been around for a long time.  It is first documented in the 4th century as a treatment for food poisoning or severe diarrhea.  Its current application has focused on C difficile infection (CDI), though its use in a number of other settings is being explored.  This includes irritable bowel syndrome and inflammatory bowel disease.

This articles makes several useful points.  In the ‘how to do it’ section, the author notes that at the NIH, donor screening includes screening for pathogens in the stool:

  • Bacteria: C difficile, Listeria monocytogenes, Vibrio cholera, Vibrio parahemoltyicus, H pylori
  • Parasites: Giardia, Cryptosporidium, Isospora (acid fast stain)
  • Viruses: Rotavirus
  • Blood: for Hepatitis A IgM, Hep B (HBsAg, anti-HBc ([gG & IgM]), HIV, Syphilis, HCV

However, the author notes that testing in the community tends to rely on screening only for enteric pathogens (stool tests only).  Donors should be excluded if they have received antibiotics in the preceding 3 months, if they participate in high-risk sexual behaviors, recent tattoo piercing, or recent incarceration.  Additional exclusions: history of IBD, IBS, immunocompromise, morbid obesity, metabolic syndrome, atopy, and chronic fatigue.

Related donors may provide a better long-term outcome.  In a recent review, FMT using a related donor yielded a 93% CDI resolution compared with 84% for unrelated donors.

Nuts and bolts:

  1. Donor is instructed to take a double dose of milk of magnesia at bedtime the night before procedure.
  2. Soft stool is passed into a clean plastic container; preference is for stool to be produced within 8 hour of FMT.  Stool does not need to be frozen or refrigerated (though can be refrigerated).
  3. Saline is added to the stool which is stirred and shaken (some use blenders, some use milk or water as suspending solutions).
  4. Typical amount of stool would be 50 g in 250 cc diluent.  For colonic administration, about 300 cc are administered in cecal region.  For duodenal administration, about 60 cc are administered.
  5. Prior to administration, it is best to filter the mixture through gauze pads to remove particulate matter that would interfere with administration.
  6. Though the author notes that there have been recommendations to prepare stool under a hood as stool is considered a level 2 biohazard, he states that this is not practical and in fact, the stool in this situation is the safest stool that gastroenterologists encounter.
  7. Recipients receive a colon lavage before the procedure regardless of route of FMT administration. If possible, all antibiotics are withheld 3 days prior.
  8. On the morning of administration, the author instructs recipient to take two lopermide tablets.

As positive experience gains in CDI, further efforts in a number of other diseases (>30 listed in Table 1 of article) with altered microbiome will be explored.  Thus far, FMT has been used in autism, fibromyalgia, metabolic syndrome, multiple sclerosis, obesity, and even parkinson’s disease.

Hippocrates stated “All disease begins in the gut.”  Given the diversity of diseases in which FMT is being examined, this sentiment may be close to the truth.

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Born this way

“Baby I was born this way” is applicable to more than just Lady Gaga.  It looks like this mantra extends to functional somatic symptoms (FSS) (J Pediatr 2013; 162: 335-42).

This study which was part of a longitudinal birth cohort study, Copenhagen Child Cohort CCC2000, included 6090 children born in a well-defined geographical area around Copenhagen, Denmark in 2000.  At 5-7 year follow-up, a random sample of 3000 members of the cohort were selected; only 2912 were included as 79 were unreachable and 9 had died.  Subsequently, 1327 had complete data and were the final study sample.

FSS were measured by the Soma Assessment Interview.  In the first 10 months of living, regulatory problems which included at least 2 of 3 problems of feeding, sleeping, or tactile reactivity predicted impaired FSS at 5-7 years with aOR 2.9.  Maternal psychiatric illness during the child’s first year of life conveyed an aOR of 7.1.

FSS (ie, headache and recurrent abdominal pain) could develop due to a number of possible mechanisms:

  • hypersensitivity to stimuli
  • autonomic hyper-reactivity
  • regulatory problems may be risk factors for mood and anxiety disorders

While the strengths of this study included prospective data collection by health professionals and a fairly large sample size, there were still numerous limitations.  Measuring regulatory problems in infancy is not fully validated.  In addition, the designation of FSS is problematic as it is difficult to fully exclude organic etiologies which could present with similar complaints.

The association of maternal psychopathology with the development of FSS in their children is of interest.  It is not clear if this risk is due to nurturing effects (i.e., child’s capacity to self-regulate) or due to nature (i.e., inherited susceptibility).

Shout out for Gluten-Free Camp

One enjoyable aspect about my work with my colleagues has been their willingness to use their free time to participate and develop programs for children.  For many years, this has included several camps at Camp Twin Lakes, particularly Camp Oasis for children with inflammatory bowel disease. Most of the physicians in our group have given their time to support this camp.  In recent years, Larry Saripkin has spent a week there every summer  and Stan Cohen really established this camp in Atlanta.  In addition, our nurses have volunteered their time as well; they stay busy attending to the medical needs of these kids so they can enjoy a camp experience.

More recently, a camp for kids with celiac disease has been started, Camp WeeKanEatIt.   Under Jeff Lewis’ direction and fundraising, this camp has been started and allows kids  (8-17 yrs) who need to be maintained on a gluten-free diet to experience camp.  Siblings are allowed to attend as well.  Don’t forget this year’s camp dates: June 23-28!

Related links:

New lipid emulsions — lacking data to support usage

According to a systematic review of the literature regarding ω-3 (n-3FA) fatty acid lipid emulsions, there is a “lack of sufficient high-quality data to support the use of parenteral n-3FA lipid emulsions in children” (JPEN 2013; 37: 44-55). Thanks to Kipp Ellsworth for this reference.

The authors of this study researched 4 databases up to March 2011 and extracted relevant studies.  Five randomized controlled trials and 3 high-quality prospective cohort studies were included.  The strength of evidence was “consistently low or very low across all lipid emulsion comparisons and outcomes.”

Specific criticisms:

  • Few studies examined important outcomes like length of hospital stay or intensive care stay.
  • There was lack of data on growth, cognitive development or potential long-term effects/harms.
  • All of the studies in children varied considerably with regard to the dosing regimens, duration of administration, and duration of followup.
  • The studies were small with sample sizes ranging from 28-91 patients.
  • The 5 RCTs had unclear risk of bias due to inadequate blinding of participants and study personnel.
  • All of the RCTs were funded by the manufacturer.
  • While some biochemical outcomes improved, no difference in mortality has been identified.  A biochemical response is a poor measure of effectiveness.  In fact, several studies have shown deterioration in liver histology and fibrosis despite improved biochemical measures in infants on Omegaven.
  • For Omegaven (fish oil) treatment, all studies used a historical control group.  In these studies, typically the Omegaven dose was half the dose of Intralipid used in the control group.

This article (in its Table 1) identifies the constituents in the commercial available lipid products which include Intralipid, Clinoleic, Liposyn II, Omegaven, SMOFLipid, and Lipoplus.  Intralipid which is widely used is devoid of substantial arachidonic acid (ARA) and docosahexaenoic adic (DHA).  This is particularly important in premature infants as noted in recent blogs:

Omegaven, in particular, and SMOFLipid, to a lesser degree, have much more AA and DHA.  As such, both of these emulsions have the potential improve vision and cognitive outcome in premature infants.

Related blog posts:

Duodenal IELs and the likelihood of celiac disease

The diagnosis of celiac disease has definitely become more complex due to the interplay of serology, genetic markers, clinical response to gluten-free diets, and histology.  The Mayo clinic pediatric experience with duodenal intraepithelial lymphocytosis (IELs) with normal villous architecture highlights this issue (JPGN 2013; 56: 51-55).

Between 2000-2009, 56 children from the Mayo clinic pathology database of duodenal biopsies (n=1290) were identified.  Among this group, 48 had serological testing for celiac disease (CD).  Ultimately, 9 were labeled with CD, though only 5 met the ‘definite’ criteria.  Other conditions that were associated with increased IELs included the following:

  • Medication exposure
  • Inflammatory bowel disease
  • H pylori infection
  • Autoimmune conditions
  • IgA deficiency

So, which patients with duodenal IELs had CD?

  • “Definite” CD was used to define patients with elevations in two different serologic markers (TTG and EMA) or those with elevation in one serologic marker along with a documented clinical response to a gluten-free diet (GFD).
  • “Possible” CD described patients with normal serology, but serologic titer and clinical response was noted on a GFD.
  • “Unlikely” CD categorized patients with two negative serology markers who had compatible human leukocyte antigen haplotype and had clinical response to GFD.

In addition, if the IELs were predominantly on the villi tips, this increased the likelihood of CD.

Related blog posts:

Three PEG Pediatric Cleanouts

Several articles highlight the use of polyethylene glycol (Miralax) as a bowel prep for children:

  1. JPGN 2013; 56: 215-19
  2. JPGN 2013; 56: 220-24
  3. JPGN 2013; 56: 225-28

These studies and the accompanying editorial (pg 115) show fairly good results with PEG cleanout regimens.

The first study compared PEG versus senna in a blinded, prospective randomized trial.  After enrolling 30 children (6-21 years of age) at a planned interim analysis, the study showed superiority of PEG (1.5 g/kg/day) when used for 2 days prior to colonoscopy.  In addition to laxatives, patients were instructed to consume full liquid diet for 2 days prior to procedure & clear liquid on day prior (up to 3 hours before procedure).  In the PEG group, good or excellent cleanout scores were noted in 88% compared with only 29% in the senna group. There were no significant adverse effects or electrolyte changes which are well-detailed in this study (Table 2).

The second study evaluated a 1-day regimen with 46 children in a prospective open-label study.  238 g of PEG was mixed with 1.9 L of gatorade and administered over several hours.  Patients (8-18 years) were instructed to take only clears after noon the day prior to procedure Only 37 (82%) were able to take the full preparation.  43 (93%) took at least 75% of the preparation.  Despite issues with tolerance and nausea/vomiting (noted in 60%), 77% were rated as having an effective cleanout.

The third study enrolled 45 children (5-21 years) in a prospective study of a 1-day bowel preparation. Patients <45 kg received 136 g of PEG solution with 32 ounces of Gatorade; patients >45 kg received 255 g in 64 ounces.  44 children completed study.  Patients were told to take PEG over 3 hours the evening prior to procedure and allowed clears until 3 hours prior to procedure.  In this group, nausea was noted in 34% and vomiting in 16%.  However, patients reported that preparation was easy in 61% and tolerable in 39%.  The quality of the preparation was considered excellent in 23%, good in 52%, fair in 23% and poor in 2%.  There were no significant electrolyte changes.

Take Home Message:

Numerous small studies show that PEG solutions can be used as a safe, effective bowel preparation in children.  Shorter duration preparations are more convenient and may result in nausea or vomiting.

In our institution, we frequently use PEG cleanouts.  However, typically our doses of PEG are lower (eg. 136-168 g) and often combined with an enema to complete cleanout process.  Unlike adult preparations, we have not instructed families in split-dose regimens mainly due to concerns about the ability of pediatric patients to adhere to these regimens.

Related blog entry:

Miralax Safety

Periodically questions about the safety of Miralax arise. Recently, several colleagues have received some questions about the use of Miralax due to information on the internet. You may want to familiarize yourself with this link due to the misinformation which is provided:

http://www.gutsense.org/gutsense/the-role-of-miralax-laxative-in-autism-dementia-alzheimer.html

Some of the misleading statements:

  • Miralax has never been tested for safety in children
  • Miralax makes one cancer-prone by leaving the colon unprotected
  • Miralax may result in severe malnutrition ..leading to Autism
  • Miralax can cause memory loss and neurologic side effects

It is true that there is not enough adequate long-term data on the use of Miralax, though there are studies showing its effectiveness/safety (see below).  However, according to the FDA, there are no neuropsychiatric warnings needed for Miralax:

As with all medications, one has to weigh the risks and the benefits.  Clearly, the risk and consequences of untreated defecation problems can be severe in some children and may have terrible adverse effects on daily living.  The known safety profile of Miralax is very good and its usage has been recommended by the American Gastroenterological Association (AGA) and by the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN) in position statements on the treatment of constipation:

An article from NY Times on this subject:

Related Blog Posts:

Related references:

-Aliment Pharmacol Ther 2011; 33: 33-40.  Comparison of golytely vs miralax.
-Gastro & Hep 2008; 4: 489.  Safety/effectiveness of PEG3350 as sole agent for cleanout in 245 adults.  Used 204 gram in 32 oz of water.
-Pediatrics 2006; 118: 528.  Data on safety and effectiveness in 79 children (39 c PEG, 40 c MOM).  PEG outperformed MOM.  compliance for PEG was 95%, after 12 months, 62% improved c PEG and 33% recovered (did not need med anymore).
-JPGN 2004; 39: 536. n=75.  good experience with infants & toddlers; 85% short-term/91% long-term success.
-JPGN 2004; 39: 106.  Miralax cleanout: 4 glasses of Miralax, clears , two doses of senna or bisacodyl, & 1 saline enema.
-J Pediatr 2004; 144: 358.  4 day cleanout with Miralax, 1.5g/kg/day; last day with clears.  No enemas given.
-Arch Pediatr Adolesc Med 2003 Pashankar DS et al; n=83. Rx avg 8.7mo. insignificant adverse effects. no loss of efficacy
-Clin Pediatr 2002; Gremse DA. Lactulose & Miralax equivalent , but Miralax preferred
-JPGN 2004; 39: 197.  Published use in infants, n=28
-JPGN 2003; 37: 329 (9A) use of Miralax to 2mo or older, n=23.
-J Pediatr 2002; 141: 410-14.  PEG 3350 at doses of 1-1.5g/kg/d for 3 days relieved an impaction in 95%.
-JPGN 2002; 34: 372-377. n=28 pts + 21 pts c MOM control.  61% vs  67% doing well at 12 month f/u.
-OnlineJournal of Digestive Health 1999; 1.  Miralax results in good long-term success without salt absorption.
-J Pediatr 2001; 139: 428-32.  Mean effective dose was 0.84 g/kg/day (range 0.3-1.4 g/k/d) n=24 (for 8 weeks) 18mo to 11 years.
-JPGN 2001; 32: 514. Safety of miralax & references.

Where is the Journal Editor?

A recent article is titled “Determination of Bone Age in Pediatric Patients with Crohn’s Disease Should Become Part of Routine Care” (Inflamm Bowel Dis 2013; 19: 61-65). (Thanks to Ben Gold for suggesting this reference.)

Does the study merit the authors’ conclusion that ‘determination of bone age (BA) should become the standard of care in pediatric Crohn’s disease (CD) patients, allowing clinically meaningful interpretation of growth…leading to improved treatment recommendations?’

No.  This small study (n=49, 84% Caucasian) simply showed that a lot of pediatric CD patients have a delayed bone age.  This is not a novel finding.

Specifically, the mean BA Z score was -1.40 ± 1.5 in this population and 41% had a BA Z score of < -2.0.  This cross-sectional study was conducted between 2007-2009.  Patients were consecutively approached for enrollment during this time period.

Clinical factors associated with delayed bone age included Caucasian race, Tanner stage 1-3, history of steroid exposure, colonic disease location, azathioprine/6-mercaptopurine usage, and female sex.  Interestingly, these variables are not entirely consistent with prior studies in which male sex was associated with delayed bone age.

The reason why the conclusion is a far-reach is that there is no data in the study showing how bone age influences any clinical decision-making in these patients.  There is no information on cost-effectiveness of their proposed “standard of care.”  There is no longitudinal data to suggest that the delayed BA or the recognition of a delayed BA  resulted in a different outcome.

My conclusion:

Many pediatric patients with CD have delayed BA and some may benefit from a BA determination.  I think extrapolating a much broader conclusion from this study is not warranted.

Vitamin D deficiency and metabolism in pediatric Crohn’s disease

As noted in previous blog posts (see links below), vitamin D has received a great deal of attention with a number of chronic diseases.  In this latest study from CHOP, the incidence and mechanisms of vitamin D deficiency in pediatric Crohn’s disease are explored (Inflamm Bowel Dis 2013; 19: 45-33).

At diagnosis (2002-2005), Crohn’s disease (CD) participants (n=78) had their serum vitamin D assays and parathyroid hormone (PTH) levels checked.  Then, these values were sequentially followed at 6 months, 12 months, and a median of 43 months later (n=52). The average age of the CD patients was 12.7 years.

Key findings:

  • 42% of CD participants were 25-OH D deficient (<20 ng/mL) with an odds ratio of 2.1 compared with controls.
  • Among patients with 25-OH D <30 ng/mL, CD patients had a lower PTH than controls.
  • At final visit, 3% remained 25-OH D deficient and PTH levels corrected.
  • Risk factors, besides CD, for vitamin D deficiency: black race (OR 10.4), visit in winter (OR 2.4), age 12 to <15 (OR 2.7), age >15 (OR 3.2).  Greater disease activity was associated with lower vitamin D levels at baseline.

Implications of this study:

  1. Vitamin D deficiency normally causes secondary hyperparathyroidism.  With newly-diagnosed CD, there was a relative hypoparathyroidism that resolved with therapy.  “It is conceivable that proinflammatory cytokines associated with CD …prevent an appropriate PTH response.”
  2. The authors state that ‘vitamin D deficiency likely contributes to the pathogenesis of CD through effects on T and B lymphocyte, macrophage, and dendritic cell regulation.”  Correcting vitamin D deficiency may improve CD treatment response in addition to potential improvements in bone health.

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