Looking behind and looking forward in EoE (part 2)

While yesterday’s article was good, today’s is really forward-thinking (Gastroenterol 213; 145: 1289-99).  Last year in this blog, I reviewed the use of microRNA for studying EoE (MicroRNA signature for eosinophilic esophagitis | gutsandgrowth), this study expands on this idea with the development of the EoE diagnostic panel (EDP) which is a 96-gene quantitative polymerase chain reaction assay.

The authors (one of whom [JG] has joined our group) used this assay initially in 15 pediatric with EoE, in 14 pediatric non-EoE, and then in a subsequent cohort of 194 pediatric and adult patient samples (fresh or formalin-fixed tissue from one esophageal biopsy).  Of the latter cohort, 91 had histologically-active EoE, 57 had either non-EoE or EoE in remission, 34 were histologically-ambiguous, and 12 had reflux.

Results -first of all you have to see the results to get the best sense of how impressive they are.  Numerous figures show the EDP depictions of patients’ EoE transcriptome patterns.

  • EDP had approximately 96% sensitivity and 98% specificity; EDP’s utility could be underestimated due to limitations in the current ‘gold standard’ for diagnosis
  • EDP can distinguish EoE in remission from healthy controls as well as identify patients exposed to swallowed glucocorticoids.  Thus, with current patients in remission, the tissue may appear healthy; nevertheless, EDP identifies molecular changes in this tissue.
  • EDP can distinguish EoE from reflux

What this study means:

  1. Currently both the diagnostic standards (eg. cutoff values for eosinophils) and remission standards remain questionable.  This molecular test has the potential to raise the standard for both diagnosis and response to treatment.
  2. EDP may elucidate differences in EoE pathogenesis which could vary from patient to patient.
  3. EDP may help in prospective trials and help in clinical practice by identifying patients who are most likely to benefit from the treatments that are available.
  4. EDP may help overcome the patchy nature of eosinophil distribution.
  5. EDP serves as a model for how molecular testing could influence many inflammatory conditions including asthma, inflammatory bowel disease and biliary atresia.

While I think this study is going to be highly influential, I have one unanswered question:  how much will it cost?  In the conclusion, the authors state “the EDP offers an accurate, rapid, informative, and low-cost diagnosis.”  Yet, the authors do not elaborate on the expense of this technology.

Related blog entries:

Looking behind and looking forward in EoE (part 1)

Two important articles are provide additional insight into eosinophilic esophagitis (EoE).

In the first (Gastroenterol 2013; 145: 1230-36), the authors performed a retrospective review of the Swiss EoE Database (SEED). This SEED should not be confused with our SEED center (Home- The SEED Center of Atlanta– SouthEast Eosinophilic ).  While the database contains 783 EoE patients, only 200 who were followed by the senior author and had complete data were included.  The enrollment period dates back to 1989.

Demographics: 153 men, mean age 39 years old, 94.5% had dysphagia at time of diagnosis and 35.5% had chest pain.  66% had concomitant allergies.

Terminology: The authors defined strictures as low-grade if a standard 9 mm endoscope could pass but met resistance, intermediate if a 6 mm endoscope could pass, and high-grade if it could not be passed with a 6 mm endoscope.

Results:

  • 37.5% (n=75) had strictures (other endoscopic findings noted in Table 2)
  • Peak eosinophil count (median): 35 proximally and 28 distally
  • Figure 2 showed the evolution of endoscopic features based on diagnostic delay.  With increasing diagnostic delay, there developed a preponderance of a mixed fibrotic/inflammatory picture whereas in those whose symptoms were of much shorter duration, the endoscopic features were often inflammatory without fibrosis.
  • For example, if diagnostic delay was between 0-2 years, then fibrotic findings were noted in 46.5%; in contrast, 87.5% had fibrotic features if symptoms had been present for > 20 years.
  • Strictures increased from 17.2% in those without significant diagnostic delay to 70.8% in those with symptoms present for > 20 years.
  • The authors note that diagnostic delay was greatest in those who developed symptoms in the first decade of life.

Study limitations: The categorization of strictures is straightforward; however, newer tools like the EndoFlip can detect esophageal narrowing more accurately.  Other limitations are related to retrospective nature of study and its reliance on patient’s reported outcomes (subject to recall bias).  Thus, the estimation of diagnostic delay may be inaccurate.

Take home message:

This article reinforces the concept that the presentation of EoE changes with time and that the long-term consequence of untreated EoE is increasing fibrosis and stricturing of the esophagus.

Related blog entries:

Picking the right diet for EoE

A study from Philadelphia/CHOP offers more insight into food selection diets for eosinophilic esophagitis (EoE) (Spergel JM, et al, J Allergy Clin Immunol 2012; 130: 461-7) –thanks to Seth Marcus for forwarding this article to my attention.

For this study, the authors examined their database of 1187 patients.  While the data was collected prospectively, this was a retrospective study.  Of this 1187, the authors excluded patients with proton pump inhibitor-responsive EoE (n=191) along with patients with more extensive eosinophilic GI diseases (n=55).

Among the remaining 941, the male-to-female ratio was 2.8:1 and the average age was 6.4 years. Concurrent atopic disorders were common: 64% had rhinitis, 50% had asthma, and 24% had atopic dermatitis.  Only 18% had no atopic disorders.

The actual number for the study though was 319.  Among the 941 noted above, 148 were receiving medications (n=130 for topical steroids), and causative foods were not identified in 474.  In some of these patients, families were content to stick with a multiple food elimination without determining with certainty which foods were truly necessary.

In less than 5% of patients, a strict elemental diet was used.  In this group, the population was younger (average 2.8 years).  Biopsy improvement was noted in “upward of 98%.”

Key findings:

  • Elimination of foods based on combined skin prick tests (SPT)/atopy patch tests (APT) had an identical response to the six food group diet –53%.  The allergy testing group had less eliminated foods (average 3.2 foods) compared with 8 food groups in SFED.
  • Elimination of milk with SPT/APT testing resulted in 77% response.  Authors note that there was a “particularly high false-negative rate (34%)” with milk testing (SPT/APT).
  • Elimination of top 8 allergens: milk, soy, egg, wheat, and meats [chicken, turkey, pork, beef] had an identical response of 77%.
  • Elimination of milk, egg, and wheat had a success rate of 48%.  Milk only elimination had a 30% response rate.
  • Most common foods by biopsy: milk (35%), egg (13%), wheat (12%), soy (9%), corn (6%)
  • Most common foods by symptoms: milk (19%), egg (11%), wheat (9%), soy (10%), beef (8%)
  • IgE-mediated foods:  milk (10%), egg (17%), soy (4%), peanut (22%)

Additional useful information in the addendum of methods notes their technique for APT testing (which is not standardized across centers).  The authors use 2 g of dry foods in 2 mL of isotonic saline solution for most foods; for milk, they use 3 g of powdered milk with 1 mL of isotonic saline.  Then these mixtures are placed in aluminum cups (6- or 12-mm Finn chambers on Scanpore).  These cups are placed on patient’s backs and removed at 48 hours and read at 72 hours.

In addition, for each food, their tables list predictive values (positive predictive value, negative predictive value, sensitivity, and specificity) for SPTs, and for APTs.  Overall, the predictive values are quite variable and much different from the general population. For example, in the general population, the negative predictive value is essentially 100% for combination of SPT/APT.

Previous related blog entries:

Choosing topical therapy for EoE | gutsandgrowth

Guidelines for Eosinophilic Esophagitis | gutsandgrowth

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

Lessons on Stature from Asthma Treated with Steroids

A study of the effects of budesonide for the treatment of asthma should be carefully considered by those of us who treat eosinophilic esophagitis with “topical” steroids; also, this study has applicability to Crohn’s disease patients receiving chronic glucocorticoids.  Mean adult height was 1.2 cm lower in the budesonide-treated asthmatics than in the placebo group (NEJM 2012; 367: 904-12).

This was the main finding at the end of the Childhood Asthma Management Program (CAMP) clinical trial.  This report examined 943 of 1041 (90.6%) participants  who had received either 0.4 mg of budesonide, 16 mg of nedocromil or placebo daily for 4 to 6 years.  Treatment with these agents began between ages 5 to 13.

The reduction in adult height was to similar in adulthood as it was after 2 years of treatment; there was not catch up growth.  With regard to the adult measurements, 96.8% of the adult women were at least 18 years and the adult men were at least 20 years of age.

Other findings:

  • Larger daily dose: each microgram per kilogram was associated with -0.1 cm drop
  • Other risk groups: Hispanic ethnic group, female sex, greater body mass index, longer duration of asthma, and higher Tanner stage at initiation

The authors note that 0.2 mg dosage of budesonide has been shown to be effective to control asthma symptoms in children 5-11 years.  The “lowest effective dose” should be used; “the effect on adult height must be balance against the large and well-established benefit of these drugs in controlling persistent asthma.”

Related links:

Looking better or feeling better in EoE?

Guidelines for Eosinophilic Esophagitis

Choosing topical therapy for EoE

The undiscovered country

String test for EoE

Gut Online First, published on August 15, 2012 as 10.1136/gutjnl-2012-303171  Furuta GT et al.  “The oesophageal string test: a novel, minimally invasive method measures mucosal inflammation in eosinophilic oesophagitis”

This study examined an esophageal string test (EST) in 41 children; 14 with active EoE, 8 with EoE remission, 4 with gastroesophageal reflux, and 15 controls.  The goal of this study was to measure eosinophil-derived proteins with an EST with a hypothesis that these proteins would correlate with mucosal inflammation as determined by biopsies.

Methods: Using a FDA approved device, Enterotest, patients were instructed to swallow  a capsule attached to a string.  Luminal secretion samples from the string were used for the EST.  The esophageal portions of the string were aided by the use of pH indicator sticks.  Patients were between 7 and 20 years of age.  The EST was placed overnight in the esophagus.  The EST was removed at the time of an endoscopy the following day.

The measured proteins included the following:

  • Eosinophil secondary granule proteins: major basic protein-1(MBP-1), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and eosinophilic peroxidase (EPX).
  • Charcot-Leyden crystal protein/galectin-10 (CLC/Gal-10)

When looking at Figure 1 in the results (full text link below), there is a striking difference in the measurement of these EoE proteins in the active group compared with the other groups.  The remission EoE group also had modest elevation of EoE proteins, particularly ECP and EDN, relative to the GERD and control groups.

Conclusions:

  • Measurement of these proteins did correlate with peak and mean eosinophil counts and distinguished active EoE from the other groups
  • EST could serve as a minimally invasive marker of for EoE activity and response to therapy.  EST would be less expensive, quicker and safer than endoscopy

Technical issues will need to be addressed to improve the applicability of EST.  For example, shorter incubation time could make the test more feasible.  Also, for younger patients, swallowing an EST/capsule will remain problematic.

Full text: http://gut.bmj.com/content/early/2012/08/14/gutjnl-2012-303171.full.pdf+html

Previous related blog entries:

Choosing topical therapy for EoE

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

Choosing topical therapy for EoE

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

Looking better or feeling better in EoE?

When seeing a new diagnosis of eosinophilic esophagitis (EoE), I often try to explain that there are two potential goals of treatment: clinical remission (improvement in symptoms) and histologic remission (improvement in appearance of esophagus with microscope).  Unfortunately, these two outcomes are not always synchronous; more proof of this comes from a recent study (Clin Gastroenterol Hepatol 2012; 10: 742-49, 750-52 [editorial]).

In this double-blind, randomized, placebo-controlled study of fluticasone in adult patients with a new diagnosis of EoE, 19 patients were treated with fluticasone (880 μg BID) and 15 patients were treated with placebo inhaler –for six weeks.  Initially, 21 patients were assigned to each group; 2 dropped out of treatment group and 6 dropped out of placebo group before completion of followup EGD.   The average age in the treatment group was 37 years versus 38 years in the placebo group.  A complete histologic response was defined as >90% reduction in mean eosinophil count; this occurred in 62% of fluticasone patients and in none of the placebo group, based on an intention-to-treat analysis.  Another measure of eosinophil activity, eosinophil-derived neurotoxin (EDN), was reduced by 81% on intracellular staining in the treatment group compared with 8% in the placebo group.  Figures 1 through 3 show this staining –it’s pretty cool!

Yet, the clinical response was not statistically different.  Dysphagia was reduced by 57% in the treated subjects compared to 33% in the placebo subjects in an intention-to-treat analysis.  Results were improved modestly in those who actually were treated: 63% (12 of 19) compared to 47% of placebo patients.  A complete response for dysphagia was noted in 42.9% of fluticasone group compared with 28.6% of control group based on an intention-to-treat analysis.  A fairly high rate of candidiasis was noted in treated patients 26%;  no placebo patients developed candida.

Another interesting finding was that among those who continued PPIs for heartburn symptoms the response to fluticasone was not improved.  40% of PPI users had a complete histologic response compared with 79% of non-PPI users.

So what are the reasons for the discrepancy between clinical and histologic response?

  • Established strictures and small-caliber esophagus may require dilation rather than medicines to relieve dysphagia
  • Esophageal fibrosis and subsequent esophageal compliance may not respond to topical therapy or take a lot longer to improve
  • Secondary candidiasis may reduce clinical response –though in this study, 5 of 6 patients with candida did in fact have symptom resolution
  • Compensatory behaviors may improve clinical symptoms –chewing food, cutting up food better, drinking more fluids, and avoiding some foods.  This may make it harder to detect important differences.

Patient information link: (Eosinophilic esophagitis – CCDHC Home)

Related posts:

Look of improvement on an EoE diet

Guidelines for Eosinophilic Esophagitis

Eosinophilic Esophagitis -Six Food Group Diet

The undiscovered country

MicroRNA signature for eosinophilic esophagitis