Category Archives: Uncategorized

Choosing topical therapy for EoE

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A brief report adds useful information for topical therapy for eosinophilic esophagitis (EoE) (Gastroenterol 2012; 143: 321-24).  This study involved 25 subjects in a prospective randomized open label design that compared budesonide delivered via either as a metered nebulized form (NEB) or as oral viscous solution (1 mg BID).  The mean age of the subjects was 35 years, 60% were male, 88% were caucasian, and all had dysphagia.

Findings:

  • Orally administered viscous budesonide (OVB) was more effective at lowering esophageal eosinophilia.  After treatment, eosinophil count per high power field was 11 for OVB compared with 89 for NEB formulation.
  • Nuclear scintigraphy showed that OVB had a significantly higher level of esophageal exposure to the therapeutic agent than NEB and did not result in lung exposure (which occurred in NEB group)
  • Both groups had improvement in dysphagia.  Poor correlation of symptoms and histology has frequently been reported.

These findings along with the fact that budesonide has less systemic corticosteroid effects, due to a high first-pass metabolism, makes OVB a logical choice for patients treated with topical steroids.

Previous related blog entries:

Guidelines for Eosinophilic Esophagitis

Looking better or feeling better in EoE?

Look of improvement on an EoE diet

Eosinophilic Esophagitis -Six Food Group Diet

MicroRNA signature for eosinophilic esophagitis

The undiscovered country

Delays in diagnosing Crohn’s disease

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Delayed diagnosis remains a problem in Crohn’s disease (Inflamm Bowel Dis 2012; 18: 496-505).  This study included a total of 1591 IBD patients (932 CD, 625 UC, 34 indeterminate colitis) from the Swiss IBD cohort study (SIBDCS).

  • Diagnostic delay in CD patients was significantly longer compared to UC patients (median 9 versus 4 months, P < 0.001).
  • 75% of CD patients were diagnosed within 24 months compared to 12 months for UC and 6 months for IC patients.
  •  Independent risk factors for long diagnostic delay in CD (>24 months)  included age <40 years at diagnosis (odds ratio [OR] 2.15, P = 0.010) and ileal disease (OR 1.69, P = 0.025)
  • In UC patients, nonsteroidal antiinflammatory drug (NSAID intake (OR 1.75, P = 0.093) and male gender (OR 0.59, P = 0.079) were associated with long diagnostic delay (>12 months)

Diagnostic delay has been a problem for quite a long time; in children, delays can worsen growth failure.  In 1988, Kanof et al reported that decreased height velocity preceded the diagnosis of CD in 88% of their patients (pediatric cohort). In addition, 42% of their population had a reduction in height velocity before intestinal symptoms were noted.

Especially when there is not a lot of colonic disease, a high degree of suspicion needs to be maintained.  This is not difficult for pediatric gastroenterologists.  For pediatricians and family physicians, the increased availability of biomarkers (Biomarkers identify patients who benefit and how) should be helpful in reducing diagnostic delays.

Additional blog entries and references:

  • Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn’s disease. Gastroenterology.1988; 95 :1523– 1527.
  • Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn’s and Colitis Foundation of America.  North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Colitis Foundation of America, Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, et al.J Pediatr Gastroenterol Nutr. 2007 May; 44(5):653-74.

IL-10 and early onset IBD

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Among physicians who take care of patients with inflammatory bowel disease (IBD), there is an understanding that the labels “Crohn’s disease” (CD) and “ulcerative colitis” (UC) are imprecise labels.  There may be many subtypes of IBD that are classified as CD or UC.  This is becoming even more clear with advances in genetics which have shown specific genetic defects that predispose to an IBD phenotype.  In fact, more than 100 genetic loci have been uncovered that contribute to IBD, more than any other complex disease (according to editorial in same issue as reference below, pgs 285-87).

Immunodeficiency disorders, like chronic granulomatous disease, are well-recognized as potential mimics for IBD. More recently, IL-10 and IL-10 recpetor genetic mutations have been associated with early-onset IBD phenotypes (Gastroenterol 2012; 143: 347-55.)

In this study, 66 patients whose IBD started before age 5 were investigated for mutatons in the genes encoding IL-10, IL10R1, and IL-10R2.  IL-10R deficiency was confirmed with functional assays of patients’ mononuclear cells.  “Using a candidate gene sequencing approach, we identified 16 patients with IL-10 or IL-10R deficiency.”  In all 16 patients, the phenotype included refractory colitis with perianal disease; symptoms developed in the first three months of life in these 16 patients.  Five of these patients improved after hematopoietic stem cell transplantation with a median followup of 2 years.

Take-home message:

Test patients with infantile IBD for IL-10 and IL-10 receptor deficiency

Contact for IL-10 testing (free):

Karoline Fiedler, Clinical Research Coordinator, IBD Program, Toronto

karoline.fiedler@sickkids.ca

http://www.neopics.com

Crohn’s disease Differential Diagnosis:

  • Tuberculosis
  • Histoplasma
  • Sarcoidosis
  • Amebiasis
  • CMV
  • C. diff
  • Klebsiella oxytoca
  • Actinomycosis
  • Vasculitis (dermatomyositis, Wegener’s, SLE)
  • FMF
  • Allergic colitis
  • Hirschsprung’s
  • Autoimmune enteropathy
  • HIV
  • Chronic granulomatous disease
  • Glycogen storage dz, 1B
  • Hermansky-Pudlak syndrome
  • Wiskott Aldrich syndrome
  • NEMO (NF-kB essential modifier) deficiency
  • Leukocyte adhesion deficiency
  • SCID
  • Behcet’s
  • FELS/hemophagocytic lymphohistiocytosis
  • Typhlitis
  • HSP
  • Solitary rectal ulcer syndrome
  • Early-onset: IL10/IL10R deficiency, XIAP, ADAM17, NCF2 gene variant

Additional references:

  • -Gastroenterol 2012; 143: 347-55.  IL-10 signaling defects and IBD.
  • -Gut 2012; 61: 1028-35.  NCF2 gene variant and IBD.
  • -NEJM 2011; 365: 1502-408.  ADAM17 deletion and IBD.
  • -NEJM 2009; 361: 2033-45.  IL-10 receptor and IBD.
  • -JPGN 2010; 51: 690.  Discusses sarcoid (check angiotensin converting enzyme, CGD, Hermansky Pudlak)
  • -JPGN 2010; 50: 99.  Perianal dz in young children may be due to autoimmune neutropenia. -IBD 2008; 14: 1443.  phagocyte dysfunction.  Also, discusses Hermansky-Pudlak, GSD 1B, chronic granulomatous disease, Chediak-Higashi, leukocyte adhesion deficiency, cylic neutropenia, congenital neutropenia
  • -Clin Gastro & Hep 2009; 7: 1037.  MRI best study for perianal fistulas.
  • -JPGN 2006; 42: 405.  Vasculitis mimicking IBD.
  • -Pediatr 2008; 121:  447.  Consider chronic granulomatous disease -particularly if recurrent.  15-18% of CGD pts with perianal abscess.  Immunocompromised hosts at increased risk along with Crohn’s patients.  However, “vast majority” do not have underlying disease.  Can treat perianal abscess medicaly in otherwise healthy infants. (Peds 2007; 120: e548).  www.pediatrics.org/cgi/content/full/120/3/e548
  • -NEJM 2005; 352: 489-94.
  • -Gold B et al. NEJM 2003; 349 (26): 2541, Table 2

Previous related posts:

Add it to the list

Upper endoscopy useful for identifying Crohn’s disease

Serology in IBD

200 years of Health Law

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“We must not see any person as an abstraction.  Instead, we must see in every person a universe with its own secrets, with its own sources of anguish, and with some measure of triumph.” Elie Wiesel

For those who want to specialize in health law quickly, a good reference is NEJM 2012; 367: 445-50 which completes the task in five pages (& includes the quote from Elie Wiesel).

  • Apparently physicians and lawyers did not get along much better in 1812 according to this article.  Thomas Percival’s original title for his influential 1803 Medical Ethics text was Medical Jurisprudence.  About half of this text is devoted to “professional duties…which require a knowledge of law.”
  • Early medical malpractice case in 1767: Slater v Baker and Stapleton.  Slater sued after treatment for his broken leg had a poor result; the jury awarded £500 (equivalent to £60,000 in 2012).
  • Coffee quack case in 1807. A “physician” claimed to cure all fevers with several concoctions, including drugs he called “coffee.”  When a patient died, it was felt that he had been poisoned by the “coffee.” The so-called physician was brought to trial but acquitted.  The judges instructions: “it is to be exceedingly lamented, that people are so easily persuaded to put confidence in these itinerant quacks.”  No adequate legal remedy if prescribed “with honest intentions and expectations of relieving his patients.”  This case led to the first physician-licensing law in 1818 (Massachusetts).

Landmark events:

  • 1905 Jacobson v Massachusetts –no right to refuse smallpox vaccine
  • 1946-47 Nuremberg trials –Nuremberg code set forth in judgement
  • 1973 Roe v Wade –right to terminate pregnancy
  • 1990 Cruzan v Director (Missouri Dept of Health) –right to refuse life-sustaining treatment
  • 1997 Washington v Glucksberg and Vacco v Quill –no right to physician-assisted suicide
  • 2012 Nat’l federation of independent business v Sebelius –upheld patient affordable care act

Do medicines work for GERD infants?

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“Absence of evidence is not evidence of absence.” Carl Sagan

If medicines work for infantile GERD, it is difficult to prove (Winter H, et al. JPGN 2012; 55: 14-20).  The cited study is the latest having difficulty proving that proton pump inhibitors are effective in infants.  In this randomized, double-blind, placebo-controlled multinational study from 33 centers, 98 infants (1-11 months) were enrolled.  My colleague, Dr. Benjamin Gold, was one of the researchers.  Initially, a 2-week open-label treatment was given which was followed by a 4-week randomized phase.   Study participants had to have a clinical diagnosis of GERD with at least one GERD symptom  –at least twice per week in a 4-week period:

  • vomiting/regurgitation
  • irritability
  • supraesophageal manifestations (cough, wheeze, stridor)
  • respiratory symptoms triggered by feedings
  • feeding difficulties

The treatment administered was weight-based dosing of esomeprazole:

  • 3-5 kg:     2.5mg
  • 5-7.5kg    5mg
  • 7.5-12kg  10mg

Daily symptoms were captured with an interactive voice response system.  Among the initial 98 patients enrolled, 80 reached the randomization phase.  During the initial 2-week period, 81 (82.7%) had symptom improvement based on physician global assessment.  During the double-blind phase, 48.8% of placebo-treated patients and 38.5% of esomeprazole-treated patients discontinued therapy due to symptom worsening.  While the time for discontinuing esomeprazole was longer in a posthoc analysis, the primary outcome, discontinuation rate, was not significantly different.

So what is the reason that this was a negative study?  While the reasons are unclear, all of the following are possible:

  • Patient selection/lack of accurate diagnosis.  Mixed-population was recruited for the study –though this type of population is similar to clinical practice.
  • Dose of esomeprazole.
  • Inadequately powered study.  If the effectiveness of PPIs is small, a much larger population is needed.
  • Maybe these agents don’t work in infants.  Infants secrete less acid than children and adults; thus, acid blockers may not work as well. (The Medical Pendulum and Gastroesophageal Reflux)

Why not give PPIs even if they don’t work?  The previous link discusses many of the potential adverse problems that are possible with medical treatment of GERD. However, even if a medicine does not harm does not mean you should do something because it ‘might’ do some good.  An example of this is the apocryphal tale of the famous pianist who died one day in the middle of a recital. (I saw this in a journal article but cannot remember the reference.)  The manager came out to announce his death.  A man in the audience shouts, ‘Give him an enema.’ Initially, the manager tries to ignore him. After the man yells this three times, the manager responds, ‘the poor man is dead…what good will an enema do?’ The voice replies, ‘What harm will it do?

Additional references:

  • -JPGN 2010; 50: 609-18. Pantoprazole helped improve symptoms but there were no significant differences compared to placebo in withdrawal rates due to lack of efficacy. n=128.
  • -NASPGHAN 2009, Abstract#21. Meds/Rx of NICU pts did not shorten hospital stay or promote wt gain, n=1149. Abstract#26. prevacid more effective than ranitidine in infants.
  • -J Pediatr 2009; 155: 601 (letter). Should not be used to treat symptoms unless proven to be reflux.
  • -JPGN 2009; 49: 498. GERD guidelines.  “In infants and toddlers, there is no symptom or symptom complex that is diagnostic of GERD or predicts a response to therapy.” Identical response to placebo (vs prevacid) in largest double-blind randomized study (54% at 4 weeks) (J Pediatr 2009; 154: 514-20.)  Reflux is “not a common cause of unexplained crying. irritability..in otherwise healthy infants.” “There is no evidence to support the empiric use of acid suppression for the treatment of irritable infants.”

“Fatal attraction”

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Today’s 33Charts topic Children and Magnets: a Fatal Attraction gives an update on rare earth magnet ingestions (neodymium) along with some other useful links.

Addendum: Also a link from NY Times on 8/17/12: http://www.nytimes.com/2012/08/17/business/for-buckyballs-toys-child-safety-is-a-growing-issue.html?_r=1&nl=todaysheadlines

Previous posts on this topic:

More on magnet ingestions

Magnet ingestion –urgent removal needed

How helpful are probiotics?

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Nobody really knows.  Claims about their efficacy are often based on poorly designed studies.  Efficacy of each strain for specific conditions and with specific dosing is often lacking.  One recent negative study demonstrates that probiotics are often not beneficial (J Pediatr 2012; 161: 40-3).

In this randomized, double-blind placebo controlled study of 106 Polish children (1-48 months of age), Lactobacillus reuteri had no effect in preventing nosocomial diarrhea in patients admitted for non-diarrheal illnesses.  While the authors contemplate that this could be due to the strain of probiotic chosen or the dose, it is clear that evidence that probiotics prevent infectious diarrhea “is still scant.”

This conclusion is backed by a large meta-analysis (JAMA 2012; 307: 1959-69).  While the study concludes that the use of probiotics is associated with a lower risk of antibiotic-associate diarrhea (RR 0.58), it predicted that the number to treat for one person to benefit would be 13.  The study was based on a systematic review of 82 randomized clinical studies.  Yet, overall the quality of the research was considered low; the studies were often had shortcomings:

  • 59 studies “lacked adequate information to assess the overall risk of bias”
  • 64 did not indicate if treatment randomization was blinded
  • 31 did not report an intent-to-treat analysis
  • 41 did not include a calculation of the study’s statistical power to detect differences
  • 17 trials were industry-sponsored and 52 did not clarify their funding/potential conflicts of interest
  • 59 did not report on adverse events specifically related to probiotic use; few trials addressed the risk of fungemia or sepsis
  • Trials rarely specified antibiotic agents; thus, it is difficult to know if a particular probiotic would be better with certain types of antibiotic therapy or duration.

Additional references/links:

  • Potential and pitfalls of probiotics with necrotizing enterocolitis
  • -JPGN 2010; 51:24. VSL#3 helpful for IBS, n=509 (4-18yr olds). 1 per day for <11yr, 2/day in 12-18yr olds
  • -Pediatrics 2008; 121:e850. Culturelle, during pregnancy and early infancy, not effective in preventing atopic dermatitis. Did increase wheezing.
  • -J Pediatr 2008; 152: 801. Probiotic helped reduce colic sx in 30 preterm infants, Lactobacillus reuteri
  • -Pediatrics 2007; 119; e124. Probiotics reduced colic in breastfed babies more than simethicone. n=83, Lactobacillus reuteri, 10-8th power per day. Decreased crying 18 minutes per day at 1 week compared to simethicone & by 94 minutes/day at 4 weeks (95% response vs 7% of simethicone)
  • -Neurogastroenterol Motili 2007 (Quigley EM, et al), 19: 166-72. Review of probiotics and IBS.
  • -NASPGHAN 2007, author: Brian Dunlap, H. Yu, Y Elitsur. abstract -most commercial yogurts have LOW concentrations of probiotics.
  • -JPGN 2006; 43: 550. Review of probiotics for specific conditions.
  • -J Pediatr 2006; 149: 367. Probiotics reduce risk of antibiotic assoc diarrhea. If 7 pts (on abx) are treated with probiotics, one fewer will develop AAD.
  • -JPGN 2006; 42: 454. Evidenced-based review of probiotics.
  • -Pediatrics 2005; 115: 1-4 & 171 editorial.  Probiotics decreased NEC in this study.
  • -Gastroenterol 2004; 126: 1620-33.  Review of probiotics, prebiotics and antibiotics in IBD.

Comparing diets in EoE

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There remains a limited number of therapeutic options with EoE.  Dietary therapy can be effective as well as burdensome.  A closer look at dietary treatment effectiveness was recently published (J Allergy Clin Immunol 2012; 129: 1570-8 –thanks to Seth Marcus for alerting me to this article).

Due to eligibility requirements, only 98 patients of an initial 513 met criteria.  The findings from this study may be difficult to generalize because of the following:

  • Highly selected patient population
  • Retrospective study.   Dietary therapy was NOT chosen randomly.
  • Study originates from a specialized center (Cincinnati) which attracts atypical cases of EoE

That being said, the study asks some important questions. What is the remission rate for skin test-directed elimination diet in comparison to six food group elimination diet (SFED) and to an elemental diet?  The SFED actually composed two groups (in my opinion, this is a significant flaw in the study design & has a limiting effect on the conclusions).  The ‘classical’ SFED (42% or 11/26) eliminated the six most common food groups (milk, soy, wheat, egg, nuts, fish/shellfish) whereas a ‘modified’ SFED (58% or 15/26)  combined the classical SFED with foods eliciting positive skin-testing.

Some of the authors terminology:

  • Complete remission: 1 or fewer eosinophils/hpf
  • Partial remission: 2-5 eos/hpf
  • Partial resolution: 6-14 eos/hpf
  • Remission: <15 eos/hpf
  • Non-remission: >15 eos/hpf

Skin prick tests (SPFs) were performed to as many as 62 foods and 11 environmental allergens and graded 0-4.  0 equated to negative control & 4 equated to histamine control -all interpreted at 15 minutes after placement.

Atopy patch tests (APTs) were interpreted at 48 hours with scoring between 0-4.  A score of 2 indicated “erythematous with generalized induration.”  Any score of 2 or higher was considered positive.

Food reintroduction process: “Food reintroductions were initiated only when the peak eosinophil count was less than 15 eosinophils/hpf. If symptoms occurred after reintroduction of a food, patients were instructed to discontinue that food, wait approximately 10 to 14 days, and then reintroduce another food…. A food reintroduction was considered successful if no symptoms were reported and the postpeak eosinophil count was less than 15 eosinophils/hpf.”

Why were so many patients excluded?  The main causes were 181 patients did not meet strict EoE criteria, 122 patients received glucocorticoids, and 52 patients had another eosinophilia-associated condition; less common reasons included patient age >21, being part of a separate drug trial, obvious noncompliance, different diet regimen, and not having 2 consecutive EGDs separated by dietary intervention.

How many endoscopies are needed for dietary therapy?   In this study, the average patient had 8.5 EGDs at Cincinnati.  The greatest number of EGDs took place among patients assigned to an elemental diet (average >11); these patients also had a longer followup period compared to the other two groups: 2.9 years compared with 1.1 for SFED and 2.1 for directed diet.

  • All three diets resulted in improvement in eosinophil count.
  • Overall Remission rates: 96% elemental, 81% SFED, 65% directed diet
  • Complete Remission rates:  59% elemental, 39% SFED, 30% directed diet

One interesting set of data is in Table 4.  This gives the pass rate for various foods with single and multiple food reintroductions.  Milk for example had a pass rate of 35% among the 17 patients who had this as a single food reintroduction.  The values ranged from a low pass rate of 29% for strawberries to a high pass rate of 78% for cocoa and 75% for pork. Soy, eggs, and wheat all hovered near 60% pass rate.

Conclusions by authors:

1. “SFED is no less successful than directed diet and consistent with unreliability of skin testing …Our data…undermine the value of skin test-directed dietary management. ” This is due to the fact that the disease mechanism is not an IgE-mediated disease (skin testing primarily detects IgE-mediated allergens).

2. Elemental diet is superior at inducing histologic remission. However, “multiple studies indicate that adherence is inversely related to the number of foods eliminated.”

Previous related posts:

Guidelines for Eosinophilic Esophagitis

Looking better or feeling better in EoE?

Look of improvement on an EoE diet

Eosinophilic Esophagitis -Six Food Group Diet

MicroRNA signature for eosinophilic esophagitis

The undiscovered country

 

More on anti-glycan antibodies in Crohn’s disease

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As noted in recent blog entry (Serology in IBD), anti-glycan antibodies have some usefulness in inflammatory bowel disease.  More data on the utility of these antibodies is available in a study which examined the presence of these antibodies in both a pediatric and adult cohort (Inflamm Bowel Dis 2012; 18: 1221-31).

Anti-L, Anti-C, anti-chitobioside (ACCA), anti-laminaribioside (ALCA), anti-mannobioside and anti-Saccaromyces cervisiae (ASCA) antibodies were tested in 131 pediatric patients (59 CD, 27 UC, 45 controls) and in 728 adult patients (355 CD, 129 UC, 244 controls).  In this study, 78% of pediatric CD patients had at least one serological marker.  ASCA was most accurate for CD diagnosis; it was present in 63% of the pediatric cohort. 

Combined usage of these antibodies helped differentiate CD from UC.  While sensitivity for detecting CD was 78% with the presence of one serological marker, the presence of three (or more) markers increased the specificity to 93% (for CD compared to UC); however, the presence of this many markers occurred in only 28%. Increasing antibody levels also correlated with complicated CD behavior, CD-related surgery and ileal disease location.