Tag Archives: Eosinophilic esophagitis

Adrenal Insufficiency due to Fluticasone in Eosinophilic Esophagitis

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A recent study (MC Golekoh et al. J Pediatr 2016; 170: 240-5) shows that adrenal insufficiency developed in 10% of patients on chronic (>6 months) swallowed corticosteroid therapy for Eosinophilic Esophagitis (EoE).

Background: 58 patients with 67% receiving fluticasone and 33% receiving budesonide.  Median age: 13.7, median fluticasone dose 1320 mcg/day, median treatment duration: 4 yrs.  For budesonide, median dose was 1000 mcg/day and median age 10.7 yrs.

Key findings with low-dose ACTH stimulation:

  • Abnormal peak cortisol (≤ 20 mcg/dL) present in 15% and adrenal insufficiency (< 18 mcg/dL)  (n=6) noted in 10%
  • Only patients receiving >440 mcg/day of fluticasone had adrenal insufficiency
  • No patients taking budesonide had an abnormal cortisol level

Commentary:

  • Higher doses of fluticasone, particularly early in treatment, has been shown to have an improved inflammatory response.  However, as with asthma therapy, higher doses increase the risk of adrenal insufficiency.
  • Adrenal insufficiency can be asymptomatic but pose a risk for life-threatening adrenal crisis.
  • Strengths of study: Fairly large cohort, endoscopic/pathologic reports available, and ACTH stimulation testing which has better sensitivity than random cortisol.
  • Limitations: Lower number of patients receiving budesonide, particularly at a higher dose.  No indication of adherence.

My take: If higher doses of fluticasone are needed for prolonged period, consider screening (endocrinology consultation) for adrenal insufficiency.

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Farjado, Puerto Rico

Farjado, Puerto Rico

Proton Pump Inhibitors Webinar

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For those who missed the live NASPGHAN webinar, it is also available on demand: Link: Proton Pump Inhibitors Webinar. CME credit is available too.

Overall, this is a terrific review and intended for a high level audience. Here are a couple of key points from the talk:

  • Dr. Jennifer Lightdale introduced the webinar.  She noted that there has been a tremendous rise in the use of proton pump inhibitors (PPIs) in children over the past 15 years, including in infants.
  • Preponderance of evidence does not support use of PPIs for reducing GER symptoms or crying in infants.
  • PPIs are extremely effective at acid suppression.
  • Excellent discussion by Dr. Rachel Rosen on Nonerosive Reflux Disease (NERD) and distinguishing this entity from erosive reflux disease, hypersensitive esophagus, and functional heartburn.
  • On a microscopic level, NERD is similar to erosive reflux with microscopic inflammation and dilated intracellular spaces.
  • With regard to testing, it is recommended that for impedance studies, that acid suppression be stopped prior due to improved sensitivity/accuracy.
  • For those at odds with their pulmonologists and ENT colleagues, Dr. Ben Gold reviewed the literature on asthma, cough, and laryngeal-pharyngeal pathology related to reflux. The sensitivity of laryngoscopic findings to identify reflux is poor.  “There is insufficient evidence to recommend for OR against the use of acid suppression therapy.”
  • Dr. Jose Garza reviewed the indications for PPI use which include eosinophilic esophagitis/PPI-REE, erosive esophagitis, NSAID prophylaxis, Upper GI bleeding, and H pylori therapy.
  • Dr. Carlo DiLorenzo provided an in-depth discussion of the potential risks of PPI therapy and explained some of the context as well as absolute risks.  He noted that besides the risk of infection, particularly C difficile, other risks demonstrated in adults have not yet been confirmed in children.
  • “Prolonged acid suppression should be used only when indicated.”  Thus, management should include strategies for treatment discontinuation in the majority of those receiving PPI therapy.

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Isla Verde, San Juan

Isla Verde, San Juan

 

 

 

 

 

 

 

 

 

Good Press for PPIs

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A lot of medical publications focus on infrequent complications of medications.  This is problematic for many who have trouble understanding absolute risks and relative risks.  If a medication increases the relative risk of a rare problem, the absolute risk to the individual remains quite low.

For proton pump inhibitors, there has been a fair amount of focus on potential complications.  In my view, some of this is due to the fact that there are many taking these medications who may not be receiving much benefit.   Many of the adverse effects for most patients would result in a low absolute risk. In fact, stopping PPIs in those who have indications for their usage could result in significantly greater harm.

For those who’ve been thinking that proton pump inhibitors (PPIs) have been getting a ‘bum rap,’ here are a few publications have highlighted their success in problems other than ulcers and gastroesophageal reflux disease.

  • AJ Lucendo et al. Clin Gastroenterol Hepatol 2016; 14: 13-22.
  • RMM van Aerts et al.  Clin Gastroenterol Hepatol 2016; 14: 147-52.

The first study, a systemic review and meta-analysis of PPIs in inducing remission for eosinophilic esophagitis (EoE).  In all 33 studies (11 prospective) of adults and children were included with 619 patients. Key findings:

  • Clinical response was noted in 60.8%
  • Histologic remission (<15 Eos/hpf in this study) in 50.5%
  • In prospective studies, once-daily therapy had similar effectiveness to twice daily (55.9% vs. 49.7%)
  • pH monitoring did not predict response to PPI therapy

My take: While the conclusion from this study (by the authors) is that PPIs should be considered a first-line therapy for EoE, they also indicate that the findings need to interpreted cautiously due to poor-quality evidence, heterogeneity of the studies, and publication bias.  Despite these limitations, most experts agree that PPI therapy should be undertaken prior to use of other treatments like diets or topical steroids for EoE.

The second study showed that patients with hereditary hemochromatosis needed less phlebotomy if they were taking PPIs.  The study was a retrospective study which divided patients into 3 groups, including a paired group of 12 patients who had ferritin levels and number of phlebotomies compared for 3 years prior and 3 years after the start of PPI therapy.  In this group, phlebotomies were needed 3.16 times per year prior to PPI and only 0.5 per year subsequently (to keep ferritin less than 100 mcg/L).  The authors note that studies have shown that PPIs reduced postprandial iron absorption.  PPIs effect on iron metabolism “acts at cellular level in the endosomes and in the stomach, and it seems to have no influence on the hepcidin regulation.”  For PPI fans, the editorial (pgs 153-55) comments that “an attractive aspect of this strategy is the safety of PPIs, which has been shown even with long-term use.’ [Aliment Phamacol Ther 2015; 41: 1162-74]

My take: While this study is not recommending that patients with hereditary hemochromatosis start PPI therapy, those who are taking PPI therapy may need less frequent phlebotomy.

So, in addition to patients with gastroesophageal reflux disease and peptic ulcer disease, patients with eosinophilic esophagitis and those with hereditary hemochromatosis often benefit from PPI therapy.

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Half Dome, Yosemite

Half Dome, Yosemite

The Story Behind a 30 Year Esophagitis Study

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A recent retrospective study ( SS Baker et al. JPGN 2015; 61: 538-40) reported on changes in esophagitis over a 30 year period at one center.  While the authors focus on the fluctuating percentage of esophagitis noted during three periods, in my opinion, they miss the opportunity to discuss more relevant findings.

Specifically, the authors note the following:

  • From 1980-88 (n=186 over 8 years) that 26.9% had esophagitis and 4.8% had >15 eos/hpf.  Normal pathology in the esophagus was noted in 73.1%.
  • From 2000-2002 (n=321 over 2 years), 41.2% had esophagitis and 8.5% had >15 eos/hpf.  Normal pathology in the esophagus was noted in 58.8%.
  • In the most recent period, 2011, (n=675 over 1 year), 31%* had esophagitis and 12.7% had >15 eos/hpf.  Normal pathology in the esophagus was noted in 69%.     *erroneously reported as 33%

What is baffling to me are the following:

  • Why the authors assert that there has been a fluctuating prevalence.  In absolute terms, the increase in cases is marked, though one can argue that in earlier periods there may have been many undiagnosed cases.
  • Why the authors do not comment on the tremendous increase in the use of endoscopy in their discussion.  In the first period, they were averaging ~23/year, the second period ~95/year and in the most recent period, they performed 675 in one year.

My take: This study shows that esophageal eosinophilia has been present for a long time and that identification of cases has increased considerably over 32 years.  In addition, the use of endoscopy has increased markedly, yet the yield of abnormal findings remains similar.

Briefly noted: C Menard-Katcher et al. JPGN 2015; 61: 541-46.  This retrospective study of 22 children showed that 55% had esophageal strictures identified by esophagram but not endoscopy.

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Bamboo

Eosinophilic Esophagitis Review -NEJM

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Good review:  Glenn T. Furuta, M.D., and David A. Katzka, M.D. N Engl J Med 2015; 373:1640-1648

A couple pointers from this review:

  • Estimated prevalence of eosinophilic esophagitis (EoE) 0.4% in Western countries.  Symptoms are often underestimated due to patient ‘accommodation’ which includes eating slowly/carefully, drinking a lot of liquids and avoiding items more prone to become lodged (meats, pills, breads)
  • Pathogenesis: “Birth by cesarean section, premature delivery, antibiotic exposure during infancy, food allergy, lack of breast-feeding, and living in an area of lower population density have all been associated with eosinophilic esophagitis.”
  • Impaired barrier function and enhanced the activity play a role in pathogenesis
  • Food allergy is a non-IgE-mediated process.  Omalizumab, an anti-IgE biologic, is ineffective in EoE and EoE can develop in IgE-null mice
  • Male predominance (3:1) suggests that there is a genetic component.
Esophagus with ringed appearance, furrowing, and loss of vascular markings

Esophagus with ringed appearance, furrowing, and loss of vascular markings

Another useful reference on Eosinophilic Gastritis in Children: Am J Gastroenterol 2014; 109; 1277-85.  This article provides data on clinical and histologic remission with eosinophilic gastritis (>70 eos/hpf), n=30 children.  “Response to dietary restriction was high” (82% clinical, 78% histologic response) Thanks to Seth Marcus for this reference.

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Useful Information on Eosinophilic Disorders

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A review (JB Wechsler et al. J Asthma Allergy 2014; 7: 85-94) provides practical advice on dietary management of eosinophilic esophagitis (EoE); the section on food reintroduction from elemental diets for patients with EoE is particularly helpful.  They start with typically less allergenic foods (group A) to most allergenic (group D) -from their Table 2:

Group A:

  • Vegetables (nonlegume): carrots, squash, sweet potato, white potato, string beans, broccoli, lettuce, beets, asparagus, cauliflower, Brussel sprouts
  • Fruit (noncitrus, nontropical) apples, pear, peaches, plum, apricot, nectarine, grape, raisins
  • Vegetables: tomatoes, celery, cucumber, onion, garlic, and other vegetables

Group B

  • Citrus fruit: orange, grapefruit, lemon, lime
  • Tropical fruit: banana, kiwi, pineapple, mango, papaya, guava, avocado
  • Melons: honeydew, cantaloupe, watermelon
  • Berries: strawberry, blueberry, raspberry, cherry, cranberry

Group C

  • Legumes: lima beans, chickpeas, white/black/red beans
  • Grains: oat, barley, rye, other grains
  • Meat: lamb, chicken, turkey, pork

Group D

  • Fish/shellfish
  • Corn
  •  Peas
  • Peanut
  • Wheat
  • Beef
  • Soy
  • Egg
  • Milk

Also, this review includes a long list of “freebie” foods allowed while on elemental diet, including artificial flavors/colors, corn syrup, oils, salt, crystal lite, and many others.

The authors note that “in our practice, the period of exclusive elemental formula is limited to 4 weeks prior to therapeutic assessment by endoscopy and reintroduction…Single foods are introduced every 5-7 days” within a group and then endoscopy after 3-4 foods are clinically tolerated.”  Foods from groups C and D are introduced more cautiously.

Also noted: HM Ko et al. Am J Gastroenterol 2014; 109: 1277-85.  This retrospective study of 30 children with severe gastric eosinophilia (mean age 7.5 years) provides a good deal of useful information.  Key point: “the disease is highly responsive to dietary restriction therapies.”  82% of patients responded to dietary restrictions and 78% had a histologic response as well.  Dietary treatments included amino acid-based diet in 6 (n=6), 7-food group empiric diet (n=6), and empiric avoidance of 1-3 foods (n=5).  Pharmacologic treatments (proton pump inhibitor or cromolyn) were attempted in a total of four patients in this series with half responding clinically and one of four responding histologically.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Acid Suppression/C difficile and Adrenal Suppression/Topical Steroids

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Briefly noted:

J Jimenez et al. (JPGN 2015; 61: 208-11) provide more data that gastric acid suppression is associated with an increase risk of Clostridium difficile infection (CDI). This was a retrospective case-control study with 138 children with CDI and 276 controls. After adjustment, acid-suppression therapy had a 1.8 Odds Ratio association with CDI.

S Harel et al. (JPGN 2015; 61: 190-3) in this retrospective ‘pilot’ study of  patients receiving topical budesonide for eosinophilic esophagitis, 6 of 14 (43%) had mild biochemical evidence of adrenal suppression, as measured by ACTH testing. Bottomline: a prospective study is likely needed to confirm or refute these findings. In the meanwhile, stress steroid coverage could be considered in patients on prolonged budesonide.

Looking Twice for Eosinophilic Esophagitis

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Not only do you have to take a lot of esophageal biopsies, now you may need to call your pathologist to make sure you do not miss a case of eosinophilic esophagitis (EoE), especially if there are mildly increased eosinophils.  At least, that’s the message I inferred from a recent study (Rothenberg ME, et al. JPGN 2015; 61: 65-8).

In this study, the researchers identified 477 biopsies from 429 patients with EoE; 316 were from “PPI confirmed patients.”

Key finding: Of the 477 biopsies, 106 had a peak count of between 1 and 14 eos/hpf cited in the pathology report.  However, 23/106 (22% with 1-14 eos/hpf) had ≥15 esos/hpf after a second review.

Overall, 5% of the 477 biopsies were mischaracterized as not meeting the threshold of ≥15 esos/hpf prior to review.  Given this frequency at a major medical center and frequent referral center for EoE, my suspicion is that the yield of a 2nd look would be at least as high in most other centers.

Take-home point: Look twice for EoE if eosinophil count is between 1/hpf and 14/hpf. Maybe some new diagnoses are being missed and maybe some of your EoE patients in histologic remission really aren’t.

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Grand Tetons from Jenny Lake

Grand Tetons from Jenny Lake

N2U -Part 3: EoE, IBD, and Cystic Fibrosis

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2015 N2U Syllabus & Presentations

EoE Dietary Pointers (Syllabus pg 83-94): Sally Schwartz, Valeria Cohran

  • Even with SFED, elemental supplements helpful
  • Drink elemental beverages from covered glass with straw (improves palatability)
  • Cross-contamination –big issue
  • Label reading critical

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IBD EEN Pointers (Syllabus pg 95-102): Rebecca Pipkorn, Justine Turner

  • Polymeric formulas –most palatable and least expensive. Oral EEN is used costly/not covered
  • EEN particularly helpful with microperforation/flare-up presentation and with infections (eg. TB)
  • EEN induces mucosal healing and improved symptoms

References:

  • Levin et al. Inflamm Bowel Dis. 2014;20:278-285.
  • Johnson et al. Gut 2006;55:356-361.
  • Sigall-Boneh et al. Inflamm Bowel Dis. 2014;20:1353-1360.
  • Wilschanski et al. Gut 1996;38543–548.
  • Critich et al. J Pediatr Gastroenterol Nutr. 2012;54: 298–305. NASPGHAN Guidelines

Conclusions:

  • Enteral therapy offers an alternative to steroids in patients with CD
  • Has potential to improve growth and IBD symptoms
  • Avoids the side effects of steroids
  • Need further research:
  1. – Unclear of the mechanism
  2. – Unclear of the best protocol
  3. – No standard protocol for reintroduction of food

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Cystic Fibrosis (Syllabus pg 34-50) Justine Turner

Case in point: 10 yo with CF and poor growth, hx/o DIOS, poor intake, and distention.  Family had refused tube feedings previously.

Key point: Long-term survival is linked to nutritional status

  • Zemel et al. J Pediatr. 2000; 137(3):374-380.
  • Stallings et al. J Am Diet Assoc. 2008; 108(5):832-839.
  • McPhail et al. J Pediatr. 2008; 153(6):752-757.
  • Sharma et al. Thorax 2001; 56:746-750.

Other Caveats:

  • Intervene early
  • Breast milk (often with supplements) is optimal for infants
  • Poor oral intake àcould need periactin and/or supplemental feeds
  • Discussion re: pros/cons of Gtubes (pg 47 in syllabus)
  • Psychology support

Nutrition Goals

  • – Normal growth and optimal nutritional status
  • – Ages 0-2 year: Weight for length >50th percentile
  • – Ages 2-20 year: BMI percentile at or above 50th percentile
  • – BMI for males:23
  • – BMI for females: 22

Nutritional assessment at every visit & review:

  • – Weight, length/height, weight for length, BMI, head circumference in infants
  • – Nutritional education & dietary counseling
  • – Review PERT
  • – Review need for micronutrient supplementation: fat soluble vitamins (A, D, E, K), Ca, Fe, Zn, Na (salt), essential fatty acids

PERT (Pancreatic enzyme replacement therapy):

  • Infants 2000-4000 U lipase with 120 mL breast milk or formula– Mouth care for infants (and breast feeding mother)
  • Children 500-2500 U lipase/kg per meal (≤10000 U/kg/day or ≤ 4000 U/g fat/day); half meal dose with snacks
  • Ideally taken with meals and orally
  • Microspheres preferred formulation
  • Acid blockade (used to optimize enzyme activity)
  • Gold standard to assess adequacy is 72h fecal fat collection

Cystic Fibrosis Related Diabetes

  • Rare before 10 years of age
  • Increases mortality risk 6-fold
  • Weight loss and pulmonary decline begin 2-4 years prior to
  • diagnosis of CFRD

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Robie House (at Univ Chicago)

Robie House (at Univ Chicago)

 

 

Predicting Response to Topical Steroids in Eosinophilic Esophagitis

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A recent study (Wolf WA, et al. Clin Gastroenterol Hepatol 2015; 13: 45-58) examined 221 patients in a retrospective cohort study to determine how effective topical steroids were in the treatment of eosinophilic esophagitis (EoE).  The authors studied these patients from 2006-2013; the majority received budesonide (63%) and the remainder received fluticasone; the typical dosing was 0.5 mg-1 mg twice daily and 440-880 mcg twice daily, respectively. 129 (58%) of the participants were >18 years.

Key findings:

  • 57% had histologic response with <15 eos/hpf
  • Refractory patients “were difficult to treat with dietary and second-line pharmacologic therapies, with less than half responding even after multiple second-line therapies.” The most successful second-line approach was diet: 6 of 16 (38%) had improved histology (<15 eos/hpf).  Higher doses of topical agents were effective in 2 of 14 (14%) and alternative topical agent was effective in 2 of 7 patients (29%).
  • Dilatation at the time of disease presentation (25% of the study cohort) correlated with poor clinical outcome.  Only 40% (20 of 50) had a histologic response.
  • High tissue levels of tryptase and eotaxin-3 increased the likelihood of a steroid response.

As this was a retrospective study, there were several weaknesses.

Take-home message: The findings from this large cohort show that more than 40% of patients did not have a favorable histologic response.  Some recent studies indicate that higher doses of steroids may be effective, but this may be influenced by the proportion of individuals with advanced fibrostenotic disease.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Chicago's Bean

Chicago’s Bean