Category Archives: Uncategorized

If I ever see an infant with Congenital Sodium Diarrhea

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If I ever see an infant with Congenital Sodium Diarrhea (CSD), I will revisit: AR Janecke et al JPGN 2016; 63: 170-6.

A couple of pointers from this article:

  • CSD represents a group of clinical conditions with high fecal sodium losses at birth  Three mutations: SPINT2, GUCY2C, and SLC9A3 account for the majority of cases.
  • IBD occurs in some of these children.
  • GUCY2C causes a secondary loss of sodium-proton antiporter 3 function related to mutations in the receptor for guanylate cyclase C (GC-C).  (I find this particularly interesting due to work in my fellowship with guanylin which binds to GC-C.)
  • SPINT2 is associated with a syndromic CSD which may include choanal/intestinal atresias, cleft palate, hypertelorism, and polydactaly.  Unlike classical CSD (due to SLC9A3), this form of CSD is characterized by associated villous atropy and some characteristic tufts.
  • Table 1 lists other causes on the differential diagnosis including microvillus inclusion disease and epthelial dysplasia (tufting enteropathy)

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Mountain Goat at Glacier Natl Park. Antenna part of a study.

Mountain Goat at Glacier Natl Park. Antenna part of a study.

Competition and Costs in HCV Market

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Following FDA approval of Zepatier (Elbasvir/Grazopresvir) (related blog post:In brief: Pediatric HCV trial, Exercise for NAFLD, and … – gutsandgrowth), it is gratifying to see reductions in the cost of HCV treatment.  Merck has priced Zepatier at $54,600 for a 12-week course which is substantially lower than Sovaldi ($84.000), Harvoni ($94.500), and Viekira Pak ($83,000).

Zepatier is indicated for genotypes 1 and 4 and can be used in patients with severe renal impairment, including dialysis. It is likely that this will pressure rival drug companies to lower their prices as well.

More information: Will Zepatier Shake Up the HCV Market? This link is to an issue of “Specialty Pharmacy Continuum” but interestingly this same story (?verbatim) was published months later by “Gastroenterology and Endoscopy New” (August 2016) without acknowledging the previous publication (by same author).

Grinnell Glacier Trail, Glacier Nat'l Park

Grinnell Glacier Trail, Glacier Nat’l Park

Safety of Fluticasone for Eosinophilic Esophagitis (Abstract)

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Doerthe A Andreae et al. The American Journal of Gastroenterology 111, 1187-1197 (August 2016) | doi:10.1038/ajg.2016.238

METHODS:

In an open-label, prospective, single-center study, we offered pediatric patients with active EoE fluticasone 2 puffs to swallow twice a day (strengths in μg/puff: 2–4 years: 44, 5–11 years: 110, ≥12 years: 220). Clinical, endoscopic, and histological assessments were performed at baseline and shortly after therapy. If histological remission was seen, fluticasone was continued with clinical follow-ups every 4 months and endoscopic and histological follow-ups yearly. Clinical scores were derived from eight symptoms (abdominal pain, nausea, vomiting, regurgitation, chest pain, dysphagia, food impaction, and early satiety). Endoscopic scores were derived from six features (rings, exudates, furrows, edema, stricture, and shearing). Scores were expressed as ratio (features present/total). In addition to peak eosinophils/high power field (HPF) (primary outcome), histological features (eosinophilic microabscesses, degranulation, superficial layering, basal zone hyperplasia, dilated intercellular spaces, and lamina propria fibrosis) were assessed. Median clinical and endoscopic scores and individual histologic features were compared over 4 time intervals: <4 months, 4–12 months, 13–24 months, and >24 months. Growth and adverse effects were monitored.

RESULTS:

We enrolled 54 patients, 80% male, median age 6.5 years (range 2–17 years), 85% atopic (57% asthma, 68% allergic rhinitis, and 31% atopic dermatitis), and 74% with food allergy. Mean follow-up was 20.4 months, the longest being 68 months (5.7 years). Esophageal eosinophil counts significantly decreased (median peak eosinophils/HPF at baseline 72, <4 months: 0.5, 4–12 months: 1.75, 13–24 months: 10, and >24 months: 12, all P<0.01). All histological features significantly decreased from baseline to all follow-up time points (all P<0.01). Lamina propria fibrosis significantly decreased (% patients with fibrosis at baseline 92, <4 months: 41, 4–12 months: 50, 13–24 months: 45, and >24 months: 39, all P<0.01). Endoscopic features improved (score at baseline 0.37, <4 months: 0.17, 4–12 months: 0.17, 13–24 months: 0, and >24 months: 0.1, all P<0.01, except at >24 months: P<0.05). Symptoms improved (score at baseline 0.22, <4 months: 0, 4–12 months: 0.11, 13–24 months: 0.11, and >24 months: 0.11, all P<0.05 except at >24 months: P=0.05). In a mixed linear regression model that accounts for correlation of repeated observations in the patient in a per-patient analysis, we found that treatment with swallowed fluticasone led to a statistically significant and sustained decrease in peak esophageal eosinophil counts. Asymptomatic esophageal candidiasis was seen in three children but resolved with anti-fungal therapy. Height and weight z-scores followed expected growth curves.

CONCLUSIONS:

We demonstrate that swallowed fluticasone is effective as a long-term maintenance therapy for children with EoE, without growth impediment or serious side effects.

My take: This post, from an abstract, shows a single-center’s experience with fluticasone. This study provides some reassurance regarding safety & efficacy when used as a maintenance medication. However, as noted in links below, higher doses of fluticasone have been associated with adrenal insufficiency.

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Bioequivalence of Biosimilars

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From Annals of Internal Medicine: Bioequivalence of Biosimilar TNF-α Inhibitors

Ann Intern Med. Published online 2 August 2016 doi:10.7326/M16-0428

Abstract:

Background: Biosimilars are of growing clinical, regulatory, and commercial importance.

Purpose: To summarize evidence about the bioequivalence between biosimilar and reference tumor necrosis factor-α (TNF-α) inhibitors.

Data Sources: PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and LILACS from inception through 13 April 2016 and ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, EU Clinical Trials Register, U.S. Food and Drug Administration, and European Medicines Agency from inception through 30 April 2016.

Study Selection: Published English-language studies of any size or design that compared the pharmacokinetics, clinical efficacy, adverse events, or immunogenicity of a biosimilar TNF-α inhibitor with a reference biologic in humans.

Data Extraction: Two reviewers independently screened titles and abstracts, extracted data from selected studies, and assessed study quality.

Data Synthesis: Of 19 eligible studies, 8 were phase 1 randomized trials, 5 were phase 3 randomized trials, and 6 were observational studies. Most phase 1 trials (n = 7) involved healthy volunteers, phase 3 trials involved patients with rheumatoid arthritis, and observational studies involved those with rheumatoid arthritis or inflammatory bowel disease. All phase 1 trials showed that pharmacokinetic parameters of the biosimilar and respective biologic were within the prespecified equivalence margin of 80% to 125%. Phase 3 trials suggested similar clinical responses and adverse events. Adverse events were usually of mild to moderate severity. Two cross-sectional observational studies showed cross-reactivity between products, whereas 4 cohort studies of patients switched from reference to biosimilar products suggested similar efficacy and safety outcomes.

Limitation: Possible publication bias, small sample sizes of many studies, and lack of published studies for several biosimilars.

Conclusion: Preliminary evidence supports the biosimilarity and interchangeability of biosimilar and reference TNF-α inhibitors.

Screen Shot 2016-09-01 at 8.58.45 PM

 

Does Reflux Lead to Increased Aspiration Pneumonia?

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This post’s title question turns out to be quite tricky.  According to a recent study (RL Rosen et al. JPGN 2016; 63: 210-17), reflux burden, even in children that aspirate did not correlate with increased hospitalization.

Here are the details:

Methods: Prospectively recruited cohort of 116 children who had both pH-impedance testing along with modified barium swallow. The authors considered pathologic reflux to have at least 73 episodes on pH-impedance or if pH<4 for >6% of study period.

Key findings:

  • There was no statistical correlation between pH-impedance study results and total number of admissions even with or without adjusting for aspiration status (and neurologic complications).

When the authors tried to reconcile these findings, they offered three competing potential explanations for these results:

  • Reflux has little impact on hospitalziations
  • Our methods for measuring reflux are not good
  • Even “normal” reflux can be a problem for those prone to complications; therefore, reflux burden is not consequential.

What is clear is that pH-impedance studies cannot predict which patients are at risk for increased complications.  This is supported by data showing that ‘reflux-related’ hospitalizations may not improve after fundoplication (Pediatrics 2006; 118: 2326-33; J Pediatr Surg 2008; 43: 59-63).  One particularly important limitation was that the cause of hospitalizations was determined by medical record review.

My take: A simple algorithm for preventing aspiration pneumonia does not exist.  Even the role of reflux testing is uncertain.

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The accompanying article guaranteed that the pizza would pass through the body within 30 minutes.

The accompanying article guaranteed that the pizza would pass through the body within 30 minutes!!!

 

Is a Gluten-Free Diet a Healthy Diet for Those without Celiac Disease?

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A helpful commentary (NR Reilly. J Pediatr 2016; 175: 206-10) on the gluten-free diet (GFD) tries to separate fact from fiction.  A few key points:

  1. There are some health problems that can occur with a GFD, particularly when the diet is started without the support of an experienced dietician. GFD foods frequently contain a greater density of fat and sugar and can contribute to obesity and metabolic syndrome.  A GFD may lead to nutrient deficiencies in B vitamins, folate, and iron.  GFD without sufficient dietary diversity may contain increase in toxin exposures (eg. arsenic, and mercury).
  2. Gluten is not toxic. “There are no data to support the theory of an intrinsically toxic property of gluten for otherwise-healthy and asymptomatic adults and children, and certain studies have specifically demonstrated a lack of toxic effects.“
  3. Most individuals with NonCeliac Gluten Sensitivity (NCGS) do not have NCGS!  First of all, many receive a GFD without proper testing to exclude celiac disease.  Secondly, most will tolerate gluten reintroduction.  In an Italian study, “only 6.6% of consecutive patients with presumed gluten sensitivity…actually had NCGS. 86% did not experience symptoms when gluten was reintroduced.”
  4. Timing of gluten introduction: “The most current understanding…in at-risk infants is that neither delaying gluten introduction from the recommended 6 months of age to 1 year, nor introducing at 4 months of age alters long-term CD risk estimates.”

My take: This is an excellent commentary.  While many people (without celiac disease) perceive benefit from a GFD, only a minority are likely  to derive better health or improved quality of life.  Those who stick with a GFD should seek the help of a well-qualified dietician.

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Glacier Nat'l Park

Glacier Nat’l Park

How helpful are serologies in pediatric inflammatory bowel disease?

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For quite some time, I have been unimpressed with the utility of serologies in distinguishing Crohn’s disease and Ulcerative Colitis.  While some of these tests claim some usefulness, when one excludes the obvious cases of Crohn’s disease (eg. perianal disease, fistulizing disease, small bowel disease), these claims seem quite dubious  Another study backs up my interpretation: L Birimberg-Schwartz et al. Inflamm Bowel Dis 2016; 22: 1908-14

This longitudinal report from the IBD Porto Group examined a multicenter retrospective cohort of 406 children with isolated colonic disease.  These children had a mean age of 10.5 years.  117 had Crohn’s colitis, 143 had ulcerative colitis, and 146 had IBD-unclassified (IBDU).

Key findings:

  • Among those with IBDU, the most prevalent serologic profile was pANCA neg/ASCA neg (41%).  34% had pANCA pos/ASCA neg, and 17% and pANCA neg/ASCA pos.
  • ANCA+: present in 43% of patients with IBDU, 64% of patients with UC, and 30% of patients with Crohn’s.
  • ASCA+ (IgA or IgG): present in 26% of  patients with IBDU, 6% of patients with UC, and 40% of patients with Crohn’s.
  • pANCA neg/ASCA pos did help differentiate Crohn’s colitis versus IBDU with 83% specificity, 96% positive predictive value; however the sensitivity was only 33% and the negative predictive value was only 13%.
  • pANCA neg/ASCA pos also differentiated Crohn’s colitis compared with ulcerative colitis with 97% specificity, and 90% positive predictive value however the sensitivity was only 33% and the negative predictive value was only 40%.
  • pANCA pos/ASCA neg did NOT differentiate well.  For IBDU versus UC, the specificity was 66%, the positive predictive value was 94%; the sensitivity was 65% and the negative predictive value was 38%.

In short, these tests generally have poor sensitivity.  If ASCA antibodies are present, which occurred in only 23%, the serology performs better but still usually not well-enough to help with big decisions. The presence of positive serology was associated with an increased likelihood of more severe disease.

Before you order IBD serology, you may want to consider whether you might use the money for this costly test in a better way.

My take (borrowed from authors): “Serology cannot routinely be recommended for differentiating between IBDU versus CC or UC as a sole diagnostic criterion given its low diagnostic utility.”

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Trail to Iceberg Lake, Glacier Natl Park

Trail to Iceberg Lake, Glacier Natl Park

More advice on Proton Pump Inhibitors

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L Laine, A Nagar. Am J Gastroenterol 2016; 111: 913-15.

This reference explains how these clinicians discuss the long-term use of proton-pump inhibitors with their adult patients.  Thanks to Ben Gold for this reference.  Here are a couple pointers:

  • “The recent studies about CKD (chronic kidney disease) and dementia, similar to many prior studies assessing PPI risk, are retrospective observational studies…This results in differences between PPI users and non-users in factors that may impact study outcomes and confound results.”
  • Gastroesophageal reflux disease: The authors suggest that PPIs for GERD can be stopped >2 weeks after symptoms resolve.  For infrequent symptoms, H2RAs, lifestyle modifications and intermittent PPIs often suffice.
  • Barrett’s esophagus: “observational sutdies suggest that PPIs may decrease progression to neoplastic Barrett’s esophagus”

WHAT WE TELL PATIENTS: “Because of inherent risk of bias and low effect sizes we cannot conclude that associations of PPIs and adverse outcomes such as dementia and CKD in recent observational studies are vailid…Nevertheless, we cannot conclude that risks do not exist…we need to ensure that benefits outweigh potential risk.  If PPIs are indicated, using the lowest effective dose and, if possible, intermittent rather than daily therapy..should decrease the risk of potential side effects.”

On the same topic, Paul Moayyedi (in Gastroenterology and Endoscopy News, August 2016): “Every study has shown that sicker patients tend to be prescribed PPIs…Sick patients tend to develop other illnesses so PPIs will be associated with about any disease you can imagine in a database.”  As such, he asserts that weak associations (OR <2) are usually due to cofounding factors.  “The only benefit [these studies]..have is that it is another opportunity to discuss with the patients about stopping their PPI therapy, as there are a significant proportion…on these drugs unnecessarily.”

purple flowers

Biologic Exposure Prenatally and Perinatally

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The widespread use of anti-TNF therapy for inflammatory bowel disease has improved clinical outcomes including fewer surgeries, hospitalizations, and complications.  One consequence of this usage has been the exposure of infants to biologics due to their usage by their mothers during pregnancy.  A recent study (M Julsgaard et al. Gastroenterol 2016; 151: 110-19) explores this topic further.

In this study, the authors prospectively followed 80 pregnant women: 36 received adalimumab & 44 infliximab. In addition, 39 received concomitant thiopurine therapy.

Key findings:

  • The time from last exposure to anti-TNF agent correlated inversely with the concentration of these drugs in the umbilical cord and in mothers at the time of birth.
  • Median ratio for infant: mother drug concentration at birth was 1.21 for adalimumab and 1.97 for infliximab.
  • Mean time for drug clearance: 4.0 months for adalimumab and 7.3 months for infliximab. Drugs were not detected after 9 months of life for adalimumab and after 12 months of life for infliximab.
  • No increased risk of adverse pregnancy outcomes were identified; preterm birth was low (n=3 or 3.8%). 48% of women experienced a disease relapse during pregnancy.
  • In this small study, the relative risk for infection was 2.7 in infants exposed to combination therapy.  Benign courses of viral infections were noted in 16 (20%) of the entire cohort and of bacterial infections in 4 (5%).

The authors recommend avoidance of live virus vaccines in biologically-exposed infants for up to 1 year unless drug clearance has been documented. Currently, this would affect only rotavirus vaccination.

My take (borrowed from editorial pgs 25-26): “For now, the sum of evidence seems to support continued use of anti-TNF therapy in pregnancy when clinically indicated and, despite measureable levels in offspring, there does not seem to be a significant clinical consequence.”

Related study: “Adverse Pregnancy Outcomes among women with inflammatory bowel disease: a population-basd study from England” Inflamm Bowel Dis 2016; 22: 1621-30. The authors identified 1969 pregnancies from a total of 364,363 singleton pregnancies.  Women with Crohn’s had increased preterm births with an Odd ratio of 1.42, babies with low birth weight (OR 1.39); women with ulcerative colitis had only a small increase risk in preterm birth (absolute risk <2.7%).

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Art at Big Creek Greenway, Alpharetta

Art at Big Creek Greenway, Alpharetta

Lower Fiber Intake May Increase Risk of Crohn’s Flare

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According to a recent study, lower fiber intake was associated with an increased risk of a flare of Crohn’s disease over a 6-month period (CS Brotherton et al. Clin Gastroenterol Hepatol 2016; 1130-36).

This study examined dietary surveys from 1619 participants (Crohn’s disease in 1130, Ulcerative colitis in 489).  All participants were considered to be in remission at baseline. The key endpoint was disease flare at 6 months which was defined as a disease activity index score exceeding remission cutoff values.

Key finding: “Compared with those in the lowest quartile of fiber consumption, participants with Crohn’s disease in the highest quartile were less likely to have a flare” (adjusted odds ratio 0.58). There was no significant association with ulcerative colitis.

The associated editorial (1137-39) notes that “among 12 RCTs that enrolled patients with Crohn’s disease, fiber did not influence disease activity in studies of induction (flare to remission) or maintenance (remission to flare)…most RCTs had small sample size.”

My take (borrowed from editorial): “A high fiber diet is likely safe in patients with IBD [in the absence of a known stricture/obstructive symptoms] and may impart a weak benefit.”  Overall, dietary approaches are gaining traction and careful evaluation of competing claims will likely be of great benefit.

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This is where I was completely soaked. Grinnell Trail

This is where (moments later) I was completely soaked. Grinnell Trail