Tag Archives: Eosinophilic esophagitis

Higher Doses of Topical Steroids for Eosinophilic Esophagitis

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A recent randomized, double-blind, placebo controlled study (Gastroenterol 2014; 147: 324-33) examined “high-dose” fluticasone propionate (FP) for patients, aged 3-30 years, with eosinophilic esophagitis (EoE).  FP patients received 1760 mcg divided into two doses for three months, then the dose was reduced in half.

Efficacy: Among the 28 FP patients, a complete remission (CR) (≤1 eosinophil/hpf on histology) was evident in 65% compared with 0% CR in 14 placebo patients.  Furthermore, partial response (PR) (multiple definitions of responsiveness -see Figure 2) evident in about 75%.  Reduction in dose to 880 mcg/day resulted in 93% of EoE participants maintaining CR or PR.

Molecular response: The authors also studied the transcriptome prospectively in these patients with the “Eosinophilic esophagitis diagnostic panel” (EDP). “A large portion of the participants receiving FP in phase 1 showed a normalized signature compared with the dysregulated screening and placebo signatures….notably, the 6 FP participants with histologic PR or no remission also had a partial reversal with a signature different from the placebo group…However, there were still a few molecular nonresponders whose signatures failed to normalized upon FP treatment.”

Based on their study findings: the authors recommend assessment at 3 months after initiation of topical steroids because “extending the timeframe for high-dose FP to 6 months does not increase remission status.”

The authors could not identify any demographics or signs/symptoms that predicted response to high-dose FP. In addition, in this small cohort, no difference in adverse effects compared to placebo were found.

My take on this study is that it raises more questions than it answers.

  • Is the higher induction dose of FP really needed or would 880 mcg/day over a 6 month period result in the same findings?
  • Is FP superior to budesonide which is considered to have less systemic absorption?
  • Should we be using higher doses of budesonide as well?
  • Would patients be better off receiving systemic steroids and transitioning to topical steroids?
  • What are the long-term consequences, good and bad, in using higher steroid doses?

Take-home message: In a carefully designed study with molecular correlation, higher doses of Fluticasone achieved high rates of complete remission in EoE patients.  Except for elemental diets, no dietary therapies have shown to have a higher response rate.

Related blog posts:

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.

 

Putting in Place a Big Piece of the Eosinophilic Esophagitis Puzzle

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A recent study (Nature Genetics 2014; doi:10.1038/ng.3033 -thanks to Seth Marcus for this reference) provides novel in-depth molecular and mechanistic information on eosinophilic esophagitis (EoE).  Though the publication and supplemental material span only 8 pages, it is packed with information and highly technical assays and thus takes an effort to work through.

The authors performed a genome-wide association study (GWAS) of SNPs (single nucleotide polymorphisms) from >1.5 million genetic markers.  In total, this study involved samples from 736 EoE patients and 9246 controls. Four prominent markers were identified at 2p23, 5q22, 8p23, adn 15q13; however, the marker at 2p23 was most highly associated with a risk for EoE.  And, 2p23 included the CAPN14 gene (best SNP rs77569859).

Key Results:

  • CAPN14 is “specifically expressed in esophageal epithelium and is dynamically upregulated as a function of disease activity.”  Though CAPN14 is expressed in other tissues, it is primarily in the esophagus and pharynx (Figure 2).
  • CAPN14 encodes calpain 14, a calcium-activated cysteine protease.  CAPN14 showed the greatest upregulation in comparison to all members of the CAPN family.  Calpain proteases mediate protein cleavage for structural proteins, signaling molecules, transcription factors, and inflammatory mediators.  The latter are “germane for allergic responses.”
  • CAPN14 levels are >2-fold increase in individuals with active EoE.
  • CAPN14 gene is modified by IL-13.

Take-home message: (from the authors) This study shows the “potential centrality of CAPN14 in the etiology of EoE….We propose a model that links the interplay of allergic sensitization with an EoE-specific, IL-13-inducible esophageal response involving CAPN14.”

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“If all you have is a hammer…”

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In my training, one of my mentors would be critical of the mentality “scope first, think second.”  He was concerned that too many gastroenterologists/pediatric gastroenterologists used endoscopy as a tool simply “because if all you have is a hammer, the world looks like a nail.”

A recent publication (Clin Gastroenterol Hepatol 2014; 12: 963-69) on first glance, however, provides ammunition to the “scope first” gastroenterologists and undermines the concept that “functional” GI disorders vastly outnumber “organic” GI disorders.  The key finding was that esophagogastroduodenoscopy (EGD) provided an “accurate” diagnosis in 38%.  This included reflux esophagitis in 21%, eosinophilic esophagitis (EoE) in 5%, eosinophilic gastroenteritis (EGE) in 4%, H pylori in 2%, celiac disease 0.6%, and Crohn’s disease 0.4%. This finding is dramatically higher than previous studies.  In fact, in a recent published study (Understanding Idiopathic Nausea | gutsandgrowth) on idiopathic nausea, a control group of patients with chronic abdominal pain had a normal endoscopy in 100%!

In this prospective study of 290 children (ages 4-18 years with a mean age of 11.9 years), the primary indication for upper endoscopy was chronic abdominal pain.  Of this 290, 216 had at least 1 alarm feature and 125 had at least 2 alarm features.  Alarm features were considered to be the following:

  • Nighttime awakening 33.3%
  • Weight loss 15.6%
  • Family history of IBD 8.4%
  • Vomiting 7.8%
  • Dysphagia 6.9%
  • Nocturnal diarrhea 6.7%
  • Gastrointestinal bleed 5.8%
  • Chronic diarrhea 5.8%
  • Unexplained fever 4.4%
  • Arthralgia 4.0%
  • Growth failure 2.4%
  • Perirectal disease 0.7%
  • Delayed puberty 0.2%

There is little debate that abdominal pain in combination with true alarm symptoms (True red flags in recurrent abdominal pain | gutsandgrowth) merits further evaluation.  The aspect of this report that is worthy of close inspection is the diagnostic yield in the 74 patients without alarm symptoms.  The authors note that 25 (33.7%) had a diagnosis established with EGD including 16 with reflux esophagitis, 4 with EGE, 2 with EoE, 1 with erosive esophagitis, 1 with celiac and 1 with H pylori.  The diagnostic criteria for EGE included ≥10 eosinophils per hpf in the stomach and ≥20 eosinophils per hpf in the duodenum.

The authors note that the diagnostic yield was based on gross endoscopic findings in procedure notes or histologic changes in biopsy reports; “final pathology report on biopsies provided the data source for histologic diagnosis.”

In my opinion there are multiple flaws of this prospective study.

1. There is a very high rate of reflux esophagitis in both the alarm group and the non-alarm group patients with chronic abdominal pain.  Of the entire cohort (n=290), the authors identified reflux esophagitis in 21% and this was “primarily histologic esophagitis.”  Furthermore, the authors state that “the presence or response to PPI therapy was not predictive of esophagitis or GERD.”  So, the obvious problems:

  • Presence of histologic reflux esophagitis varies widely based on the interpreting pathologist.  In a prospective study, more than one pathologist interpreting the histology would be useful.
  • Presence of histologic reflux esophagitis does not exclude the likelihood of coexisting functional disorders (related blog post: Why didn’t patient with documented reflux get better with PPI …).  As a practical matter, “slight” or “focal” esophagitis on histology has questionable real-world relevance in pediatric gastroenterology.
  • The authors acknowledge, “current expert consensus indicates that histology has limited value in evaluating pediatric GERD.”  Yet this diagnostic finding is one of the reasons why the authors claim that EGD is so valuable.

2. In the entire cohort, the authors try to validate their findings by indicating that identification of a diagnosis led to medical therapy that was “effective in approximately 67%” of children with short-term followup. (Only 81% had short-term followup outcomes available).  Yet, there is no control group.  How many children with chronic abdominal pain will improve for a short period without an EGD-based diagnosis?  The answer: a lot of them.

3. Limitations include selection bias toward those with more severe symptoms or alarm symptoms.  In addition, this study included only a small number who were considered to have no alarm symptoms.  Finally, the short-term followup makes conclusions about the response to therapy questionable.

This study will be a useful reference for any pediatric gastroenterologist who wants to justify the need for an endoscopy.  The authors note “the majority of children in our study (93%) met criteria for functional gastrointestinal disorders, and a significant proportion (38%) still had significant histologic findings.  Therefore, we conclude the Rome III criteria alone are not sufficient to identify children who require upper endoscopy, and screening for alarm symptoms has limited utility.”

In my opinion, the reliance on histology as well as selection bias weaken the findings of this study.  If a patient with a histologic diagnosis of reflux (or several other entities) and a presentation of chronic abdominal pain does not improve, the pediatric gastroenterologist should remember that only “a poor carpenter blames his tools.”

Bottomline: EGD remains an important tool in evaluating abdominal pain.  However, I think this study substantially overestimates its utility.

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The Latest on EoE and PPI-REE

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A recent study shows similar clinical, endoscopic and histologic findings between eosinophilic esophagitis (EoE) and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) (Aliment Pharmacol There 2014; 39: 603-08 -thanks to Seth Marcus for this reference).

The authors used two databases: one from Walter Reed and one from the Swiss EoE database.  All of these patients were >/=18 years.  Response to PPI was defined as achieving less than 15 eos/hpf and a 50% decrease from baseline following at least 6-weeks of PPI treatment.

Demographics: 63 EoE patients, 40 PPI-REE, mean age 40 years (75% male, 89% Caucasian).

Findings:

  • Similar dysphagia 97% vs. 100% (in EoE and  of PPI-REE cohorts)
  • Similar food impaction 43% vs. 35% (in EoE and  of PPI-REE cohorts)
  • Similar heartburn 33% vs. 32% (in EoE and  of PPI-REE cohorts)
  • Similar duration of symptoms: 6.0 years vs 5.8 years (in EoE and  of PPI-REE cohorts)
  • Similar endoscopic findings too: rings 68% in both groups, furrows 70% in both groups, strictures 49% vs 30% (in EoE and  of PPI-REE cohorts)
  • Similar histology: proximal esophagus 39 vs 38 eos/hpf and distal esophagus 50 vs 43 eos/hpf

Take-home message: EoE and PPI-REE are very similar in presentation and indistinguishable without a PPI trial.

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How Common is Eosinophilic Esophagitis?

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There have been numerous epidemiologic studies regarding eosinophilic esophagitis.  A recent summary of a recent study (Clin Gastroenterol Hepatol 2014; 12: 589-96) has been posted on the AGA Journals Blog.  Here’s the link to the full summary:  EoE Prevalence AGA Journal Blog

Here’s an excerpt:

Eosinophilic esophagitis (EoE), which was barely recognized 20 years ago, affects at least 150,000 people in the United States, with three-quarters being adults, report Evan Dellon et al. in the April issue of Clinical Gastroenterology and Hepatology.

EoE, also known as allergic esophagitis, is an allergic inflammatory disease characterized by increased numbers eosinophils in the esophagus. Symptoms include difficulty swallowing, food impaction, and heartburn…

They found that despite its relatively recent description, EoE is frequently diagnosed in the US, with an estimated prevalence of 56.7/100,000 persons. The mean age of patients, surprisingly, was 33.5 years; 65% were male, 55.8% had dysphagia, and 52.8% had at least 1 other allergic condition. Prevalence peaked in men 35–39 years old (see figure).

EoE Prevalence by Age

Dellon et al. identified patients based on the International Classification of Diseases (ICD), 9th revision code for EoE (530.13). They state that this prevalence could be an underestimate, because knowledge of the code and recognition of EoE are increasing…

Take home point: This study shows that EoE in adults and in children is much more common in males than females, especially in those with other allergic diseases.  Given the frequency of those with mild symptoms, the prevalence data are likely to be huge underestimates.

Related blog posts:

 

Eosinophilic Esophagitis and Psychosocial Dysfunction

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There are many medical challenges in treating patients with eosinophilic esophagitis (EoE) and this has been discussed extensively in this blog (some links below).  What is striking in managing these patients and families is how often there are significant psychosocial problems.  Does this disorder serve as an excuse for other issues? Does the altered diet create enormous stress and isolation? Is the diagnosis of EoE an epiphenomenon for many of these patients?

While these questions are not answered, a recent retrospective study from a tertiary care center does provide some data on the frequency of psychosocial dysfunction in children and adolescents with EoE (JPGN 2013; 57: 500-05).

Psychosocial evaluation was offered as part of these patients’ clinical evaluation; this took place in 64 of 152 patients during the study timeframe.  Subsequently, a retrospective review of these patients, who had been offered a 1-hour behavioral health assessment by either a psychologist or social worker, were analyzed.

Key findings:

  • 69% had some psychosocial impairment
  • 64% had social difficulties
  • 41% had anxiety
  • 33% had sleep difficulties
  • 28% had depression
  • 26% had school problems
  • 44% had adjustment problems; this was more common in older children and in children with gastrostomy tubes

The main limitations of this study are its retrospective nature and the fact that only a minority of patients were analyzed; the latter indicates a high likelihood of a selection bias. The severity of EoE was not correlated with these problems, but could have been higher  at a tertiary center.

Take-home message: As with other chronic diseases, EoE patients have frequent psychosocial health problems –this study starts to define the extent of the problem.

Looking behind and looking forward in EoE (part 2)

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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:

PPIs -another reference for EoE

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“The outcome of patients with oesophageal eosinophilic infiltration after an eight-week trial of a proton pump inhibitor”

  1. G. Vazquez-Elizondo1,
  2. S. Ngamruengphong1,
  3. M. Khrisna2,
  4. K. R. DeVault1,
  5. N. J. Talley1,
  6. S. R. Achem1,*

Article first published online: 5 OCT 2013

DOI: 10.1111/apt.12513

Link to article: bit.ly/18bA3SS (from John Pohl’s twitter feed)

Methods: Sixty consecutive symptomatic patients with documented oesophageal eosinophilia received open-label omeprazole 20 mg orally twice daily before meals for 8 weeks.  Mean age 48.7 years (18-79).

Results: Clinical improvement occurred in 43 (71.6%), endoscopic signs were reduced in 34 (61.8%) and normalised in 12 (21.8%), and histologically, 34 (56.6%) improved, while 15 (25%) obtained complete resolution. Overall, 22 patients (36.7%) obtained both complete clinical and histological remission

Additional related blog entries:

Nexium versus Fluticasone for EoE

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As noted in previous blog posts (EoE: Drugs, Diets, Dilatation and PPI-REE | gutsandgrowth, EoE –Journal Club (Part 1) | gutsandgrowth, and EoE –Journal Club (Part 2) | gutsandgrowth), proton pump inhibitors are recommended as 1st line therapy in suspected eosinophilic esophagitis (EoE) for several reasons.  Besides the potential for gastroesophageal reflux to cause esophageal eosinophilia, there has been recognition of PPI-responsive eosinophilic esophagitis (PPI-REE).  In adults, the response to proton pump inhibitors, both clinically and histologically, is likely higher than in children; nevertheless, in children it is anticipated that 20-40% of patients with suspected EoE will have a histological remission with PPI therapy.

A recent study in adults suggests that PPIs may in fact outperform topical steroids (Am J Gastroenterol 2013; 108: 366-72).  Thanks to Ben Gold and Seth Marcus for identifying this reference.  This study enrolled 42 patients: 90% male, 81% white, mean age 38 years. It was a prospective single-blinded, randomized controlled trial with newly suspected EoE; half of the patients received esomeprazole 40 mg daily and half fluticasone swallowed aerosol 440 mcg twice a day.  After 8 weeks, all patients had repeat endoscopy; a total of eight biopsies were obtained –four at two locations: 15 cm above LES and 3 cm above LES.  In addition, at the start of the study, patients also underwent 24-h pH/impedance monitoring.  4 of the 21 patients in each group had abnormal degrees of gastroesophageal reflux/gastroesophageal reflux disease (GERD).

Study characteristics note that 62% of patients had coexisting atopic disorders.

Results:

  • There was no significant difference in esophageal eosinophilia response with 19% of the fluticasone and 33% of the esomeprazole achieving an eosinophil count < 5/hpf (P=0.484)
  • In patients with coexisting GERD, all 4 esomeprazole patients achieved histologic remission  compared with none of the fluticasone-treated patients.
  • When the GERD patients were excluded, the histological remission was quite similar: 24% with fluticasone and 18% for esomeprazole.

Overall, this study population had a lower rate of response to topical steroids than in multiple previous studies.  More typically, response rates of ~50% have been reported; however, studies have shown lower responses in some adult studies.  Variability in response could be related to multiple factors included dosage, duration, delivery, and definition of response.  In addition, population characteristics included disease duration and frequency of underlying atopic disease and GERD play a role.

Take-home points: Although this is a small study, it reinforces the fact that PPIs induce a histological response and clinical response in some patients suspected of having EoE regardless of whether GERD is present.  PPIs are considered 1st line therapy.  Topical fluticasone had a lower response rate in this study.  However, in clinical pediatric practice, topical steroids are effective in about 50% of patients.

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