Early antibiotic use and the development of inflammatory bowel disease

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Another study adds weight to the idea that early antibiotic use may increase the risk of developing inflammatory bowel disease (IBD) (J Pediatr 2013; 162: 510-4).

Using a nested case-control design, the authors matched 2377 controls to 294 children with IBD in a population-based database from Manitoba, Canada.  Specifically, the authors looked at the frequency of otitis media diagnosis and the likelihood of subsequent IBD.  By age 5 years, 89% of IBD cases had at least one diagnosis of otitis media, compared with 82% of the controls.  Despite the high frequency in both groups, the authors determined that individuals with a diagnosis of otitis media before age 5 years were 2.8-fold more likely to be an IBD case.

Some of the strengths of this study included the fact that it was a population-based analysis dating back to 1984 and likely captured almost all pediatric IBD cases (<19 years).  Nearly all physicians in Manitoba submit billing claims to a single publicly funded source.  Due to the nature of administrative data, this eliminates recall bias.

However, administrative data have several limitations as well.  Other confounding conditions may have been present and not identified; this could include family history and autoimmune diseases.

The authors “suspect” that the linkage between otitis media and IBD relates to the usage of antibiotics and subsequent alterations of the intestinal microflora.  Otitis media may serve as a “sensitive proxy measure” of antibiotic use.  Also, as boys are more frequently treated for otitis media, this may relate to the generally higher incidence of pediatric IBD in males.

For anyone interested in the association between antibiotic exposure and IBD, this study is useful and provides a number of references as well.

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Does negative testing reassure patients?

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Probably not according to a recent study (JAMA Intern Med, published online Feb 25, 2013, d0i:10.1001/jamainternmed.2013.2762).

Citation: A Rolfe, C Burton. JAMA Intern Med. 2013;173(6):407-416. Open access! Reassurance After Diagnostic Testing With a Low Pretest Probability of Serious Disease

In this study, the authors systematically reviewed the literature and, after screening 9742 studies, identified 14 randomized controlled trials (n=3828 patients) which met inclusion criteria, including the following:

  • Randomized control trial
  • Adult participants with symptoms indicating a low probability of serious disease

Studies were excluded if they were not published in a peer-reviewed journal or if they were undertaken in a tertiary care setting.  Eight trials involved diagnostic testing for dyspepsia (mainly endoscopy), three involved radiography for back pain, and the other three included testing for chest pain, headache and palpitations.  Long-term follow-up varied from 4 to 18 months.

Key Findings:

  • Patients’ illness concern (odds ratio 0.87 in three trials) and anxiety (standardized mean difference 0.06 [-0.16 to 0.28] in two trials) were not reduced in the short or long term.
  • No overall long-term effect on symptom persistence was noted (odds ratio 0.99)

Limitations:

  • The authors examined only reassurance for patients, not for physicians.
  • Participants were not blinded
  • Overall, small number of study participants

In the discussion, the authors note that observational studies “suggest that illness concerns reappear within hours of receiving a normal (negative) test  result.”

For pediatric gastroenterologists, the conclusions from this article add another wrinkle when deciding how much workup is indicated for conditions like recurrent abdominal pain.  Previous data indicate that maternal anxiety is the most consistent predictor of outcome for recurrent abdominal pain (Acta Paediatr 2007; 96: 697-701); this study does not address whether patient proxies are reassured by negative testing.  And, other studies have shown that patients rate their care higher after diagnostic testing (Don’t miss the gorilla! | gutsandgrowth).

As a fellow, I was told: “Don’t just do something, stand there” from Bill Balistreri; he also recommended avoiding the mentality of “Scope first, think second.” While this current study suggests that there is a lack of long-term benefit when testing is done primarily for reassurance, convincing families that their child does not need testing is often difficult.

Global Justice and Vaccine Policy

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I definitely was piqued by the editorial titled “Global Justice and the Proposed Ban on Thimerosal-Containing Vaccines.” (Pediatrics 2013; 131: 154-156) I wondered how vaccine policy could affect global justice.

In high-income countries, vaccines have shifted increasingly to preservative-free single-dose vials.  Whereas in poorer countries, vaccines have continued to rely on multidose vials which frequently contain thimerosal as a preservative.  The move away from thimerosal which contains ethyl mercury “was a precautionary move in response to theoretical concerns, now known to be unfounded.”

Currently, a multinational environmental treaty is close to finalization and this treaty aims to restrict human and environmental exposure to mercury.  The World Health Organization and the broader public health community have recommended that thimerosal be exempt from the treaty to avoid disruption in the global vaccine supply.  However, some nongovernmental groups have objected to the use of thimerosal in poorer countries when it has been phased out in wealthier countries.

Why Thimerosal Should be Exempt from this Ban:

  • No credible scientific evidence of any risk to human health from thimerosal
  • Vaccines with thimerosal are used in >120 countries to immunize ~84 million children every year.  It is estimated that these vaccines save 1.4 million children every year.
  • Potential vaccines affected include hepatitis B, tetanus, and diptheria-tetanus-pertutsis
  • “Although there are other preservatives…, none are yet viable alternatives to thimerosal”

The individuals and organizations who have opposed thimerosal come from wealthier countries and would not suffer the consequences of a potential ban.  “Where’s the justice in that?”

Related references:

  • Pediatrics 2013; 131: 149-151. Public health experts recommend the ongoing use of thimerosal as a preservative.
  • Pediatrics 2013; 131: 152-153.  Provides context for previous AAP joint statement on thimerosal in 1999.

Related blog entry:

Vaccine successes and ambitions | gutsandgrowth

And the Best Prep is…

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A meta-analysis has concluded that a 4-Liter split-dose polyethylene glycol prep is best (Clin Gastroenterol Hepatol 2012; 10: 1225-1231).  This is an expected finding and has been discussed previously on this blog (see below).

What is unexpected is the tremendous heterogeneity in studies of bowel preparations. For this study, the investigators identified 1123 potentially relevant references.  Almost all of these were excluded due to criteria which required 1) randomized control trial, 2) English-based language, and 3) specific study design issues.  Thus 9 studies with 2477 patients met inclusion criteria.  Mean age of patients in these studies were 52-59 years.

The pooled odds for excellent or good bowel prep quality for 4-L split-dose PEG was 3.46 compared with other methods.  The comparison regimens included non-split dose PEG, 2-L split-dose PEG, 3-L split dose PEG, Miralax preps (64 oz split dose with or without stimulants).

While the prep results were generally more favorable, there were no differences in other adverse effects, such as cramping, compliance, or overall experience.

Related blog entry:

  • split-dose PEG | gutsandgrowth This blog entry discusses a specific prep, describes the Ottawa scale, and provides additional references. In addition, includes a link to Dave Barry’s column on colonoscopy.

Will salt intake make you fat?

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Maybe.  According to a recent study (Pediatrics 2013; 131: 14-20), salt intake is associated with consumption of sugar-sweetened beverages (SSB); hence, it might make you fat.

This cross-sectional study used data (4283 participants, ages 2-16 years) from the 2007 Australian National Children’s Nutrition and Physical Activity Survey.  Calculation of dietary intake (salt, fluid, sugary beverages) was determined by looking at two 24-hour dietary recalls.

Each gram of salt was associated with a 46 gram intake of fluid.  Of those who took SSB (n=2571), salt intake was associated with increased consumption of SSB; each gram of salt was associated with a 17 gram increased intake of SSB.  Participants with SSB intake of more than 1 serving (≥250 g), in turn, were 26% more likely to be overweight/obese (odds ratio 1.26).

Study limitations included the following:

  • 24-hour dietary recalls which likely underrepresented salt intake
  • Salt intake may be clustered with other ‘unhealthy’ dietary habits.  Thus, it may be a marker for undesirable diet rather than a causal factor.

Conclusion: Besides lowering blood pressure and lowering the risk of kidney stones, reducing salt intake may help with obesity prevention.

Related blog post:

Don’t miss the gorilla!

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A recent narrative on improving value in health care (NEJM 2013; 368: 959-62) made use of a few psychological experiments to make some excellent points.

The first experiment asked the study participants to focus on a video and to count the number of passes for a team of three basketball players dressed in white while another three-player team dressed in black also played.  “During the video, a woman in a gorilla suit walked across the screen pounding her chest, remaining there for 5 seconds….Consistently, about 50% failed to notice the gorilla.”  Afterwards, when shown the video a second time, many of those who did not see the gorilla insisted that the video had been altered.

The second experiment involved perception.  “One group was initially shown a blurry image of a dog.  Then both groups were shown the exact same image, less blurry.  Those seeing the image for the first time had a much easier time recognizing it as a dog than those who had received previous ambiguous information.”  So, like those in the first experiment who did not  see the gorilla, participants are reluctant to change their opinion even when better information becomes available.

The author notes that the ‘value narrative’ can split patients and physicians into separate teams.  For physicians, value suggests avoiding overuse and providing evidence-based care.  For patients, value means enhancing their experience and catering outcomes that matter to them.  There is a study which shows that patients rate their care as better if they went to an ER for abdominal pain and underwent a CT scan (regardless of whether it was indicated).  Similarly, for back pain, two studies have shown that patients are far more satisfied with their care if they undergo an MRI.

The implications of these experiments on perception is that value in health care needs to be more transparent.

  • “We must admit that turning health care into a customer-service industry may to some extent undermine the delivery of evidence-based care.”
  • We actually know very little “about patients’ values and about how they should or might influence our decision-making.”
  • If we want to control costs and improve quality, “it will first require a look at the whole picture — and then a willingness to believe what we see.”

Can Hepatitis C really be cured?

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While many have equated a sustained virologic response (SVR) as a cure for hepatitis C virus (HCV), there have been concerns about “occult” hepatitis C.  A new study indicates that in the vast majority of patients with an SVR, there is “no evidence of ongoing HCV replication…and no evidence that HCV replicates in PBMCs of chronically infected patients” (Hepatology 2013; 57: 483-91, editorial 438-40).

There has been no disagreement that an SVR is associated with improved liver histology, improved clinical symptoms, often a reversal of fibrosis, and lower risk of hepatocellular carcinoma.  However, the study and the accompanying editorial summarize the disparity in studies about the potential for occult HCV and how the virus has been identified in the peripheral blood mononuclear cells (PBMCs) and livers of patients who have had an SVR.

The study examined 67 chronic HCV carriers and examined the liver and other tissues of 2 spontaneously recovered chimpanzees.

Key findings:

  • The authors confirm that HCV RNA can be detected in PBMCs in chronic HCV carriers, but only as nonreplicating virus; therefore, it is probably not harmful to the host or to others.
  • Healthy controls had HCV passively adsorbed to PBMCs in vitro becoming indistinguishable from the HCV RNA in PBMCs of chronic HCV carriers
  • HCV RNA could not be detected in the PBMCs of 59 presumed recovered subjects using a highly sensitive nested PCR assay (measure down to 10 IU)
  • In total, this study and others support the likelihood of absolute HCV clearance in most patients with either spontaneous or treatment-induced recovery

Editorialist recommendation: “it seems appropriate to perform virology and biochemical screening annually…particularly if…there was histologic evidence of fibrosis or cirrhosis”

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Update for Peutz-Jegher Syndrome

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A recent case series provides some useful insight into this rare condition (JPGN 2013; 56: 191-95).  Peutz-Jegher syndrome (JPS) has an incidence between 1 in 8500 to 1 in 120,000.  It is caused by a germline mutation in the STK11 gene.  It is associated with a serine threonine kinase that functions as a tumor suppressor.

14 children were identified through a medical records review at the Children’s Hospital Colorado between 2000-2011.  Inclusion required 2 or more of the following criteria:

  • 2 or more characteristic hamartomatous polyps of the small intestine
  • typical mucocutaneous pigmentation
  • positive family history (absent in about 25% of cases historically)

Results: Median age at first clinical evaluation was 4.5 years.  Intussusception was noted 7 times in 5 children (ages 5 to 16 years). Surgical reduction was required in 5 of the events. Polyps were found in the stomach/duodenum in 5 (36%), small bowel in 7 (50%), and colon in 3 (21%). Sertoli cell tumors was identified in 2 of the 10 boys at ages 8 years and 11 years.

Based on their experience, the authors suggest the following:

  • Initial screening start at age 4-5 years of age.  They recommend capsule endoscopy, upper endoscopy, and colonoscopy (CE/EGD/colon) as initial screen.  Then, they suggest repeating every 1-2 years until no polyps and then every 2-3 years.
  • In boys, they recommend breast exams for gynecomastia and testicular exams annually to screen for Sertoli cell tumor.  In girls, monitoring for precocious puberty and if present, then further evaluation for Sertoli cell tumor.

Given the small size of their cohort and the likelihood that asymptomatic children may not have been seen, it is too early to know if the approach recommended by the authors is justified.  Will earlier screening result in any long-term benefit &/or reduce complications related to JPS?

SFED works for EoE!

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A recent study confirms that an empiric ‘6-food elimination diet’ (SFED) works in adults  with eosinophilic esophagitis (EoE) as well as it has been shown to work in kids (J Allergy Clin Immunol 2013; 131: 797-804)).  Thanks to Seth Marcus for this reference.

This Spanish study recruited 67 consecutive adult patients (17-60 years) who were treated with an exclusive diet which eliminated milk (avoided goat’s milk too), wheat/cereals (avoided rice and corn too), eggs, fish/seafood, legumes/peanuts, and soy for 6 weeks.  Subsequent rechallenge followed with repeated endoscopies every 6 weeks.  A food was considered a trigger for EoE if eosinophilic infiltrate ≥ 15 Eos/hpf after reintroduction.

Prior to reintroduction, 73% (n=49) responded to SFED with peak Eos < 15/hpf. Among responders, 37 patients achieved a complete response with Eos 0-5/hpf.  Subsquently rechallenges were instituted and 42 patients completed this part of the study. A single food was identified in 36%, 2 food triggers in 31%, the remainder had at least 3 food triggers.  Cow’s milk was the most common food trigger, in 62%, followed by wheat (29%), eggs (26%), and legumes (24%).

Allergy testing (ImmunoCap IgE-based testing, and skin prick testing) showed no concordance with food reintroduction challenge results.  All patients maintained on avoidance of offending foods maintained remission for up to 3 years.

In the general scheme of food reintroduction, it is interesting that the authors often tested for wheat and milk first.  Also, the Table 1 listed numerous characteristics of responders and nonresponders and none of these had a significant predictive effect.  This table listed symptoms including dysphagia, vomiting and pain, caliber of esophagus, mucosal appearance, atopic history, atopic family history, and eosinophil counts.

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Off-label medications in pediatrics

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In the U.S., multiple legislative changes have been improving the information available for off-label use of medications (JPGN 2013; 56: 113-4).

The Pediatric Research Equity Act (PL 108-155) and the Best Pharmaceuticals for Children Act (PL 107-109) help the Food and Drug Administration (FDA) promote pediatric trials and better information.

  • Pediatric data must be included in labeling whether results are positive, negative or inconclusive
  • If pediatric trials are not completed because the drug would be ineffective or unsafe, this information must go into labeling
  • Public internet posting of certain FDA pediatric reviews is required regardless of whether the trials led to an approval

Despite these improvements, the data may be difficult to interpret.  The authors of this commentary note that only “48% of trials of products that had pediatric safety information added to the product’s labeling were reported in the peer-reviewed literature.”  Furthermore, in about half of the published articles, the studies did not emphasize the same information as the FDA labeling.

Even when a fair amount of data is provided, it is frequently ignored.  A specific example given by the authors: lansoprazole. Lansoprazole is not approved in patients younger than 1 year and labeling describes a negative trial in this age group. Yet, in the U.S., lansoprazole was dispensed off-label in this population approximately 358,000 times in 2010.

Pharmaceutical companies benefit whether the prescription is for an approved indication or for an off-label use.  Even with approved uses, there have been substantial concerns about adverse effects.  The likelihood of more risk and less benefit is much greater for off-label use.

So with the next prescription, it might be worth thinking about whether the medication works, whether there is sufficient data to support an approved indication, and how much risk is involved.

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