Brge in Child

Controlling Esophageal Disease in Children Beyond the Acid
Chair:
Benjamin D. Gold, MD
Faculty:
Samuel Nurko, MD Donald Castell, MD Glenn T. Furuta, MD
(Dr. Gold) Welcome, and thank you for joining us this evening for our symposium titled Controlling Esophageal Disease in ChildrenBeyond the Acid. I am your chair if you will for this evening, and I am joined by 3 esteemed faculty: on my far right, Dr. Donald Castell; next to him, Dr. Samuel Nurko; and to my immediate right, Dr. Glenn Furuta.
Learning Objectives
Differentiate between motility-related, inflammatory, and acid reflux disorders that contribute to esophageal disease in children Discuss the mechanisms of acid and nonacid reflux in GERD Review recently published literature on the available therapeutic options for both adults and children with GERD Provide an overview of eosinophilic esophagitis in children and its relation to acid refluxassociated and allergic inflammation
There are a few learning objectives; again, because this is CME accredited, there are some tasks that we do want to accomplish during the course of the presentation. What we would like to do is: To differentiate between motility-related, inflammatory-related, and acid reflux disorders that contribute to esophageal disease in children. We would like to discuss the mechanisms of acid- and nonacid-related reflux. I think you are in for a treat tonight because we really do have true experts in this disease that not only wrote the textbooks but really have done the seminal studies, both in adults and in children, to help us understand how to differentiate between these 2 entities. We will look at recently published literature and available therapeutic options for both the adult and pediatric population. Finally, providing an overview of eosinophilic esophagitis. Again, many of you know Dr. Glenn Furuta, who is one of the conveners of the first FIGER meeting last year and the lead author on the recent consensus paper published in Gastroenterology just this past month. I think you are in for an exciting evening with some very important, some exciting, and controversial information that we will cover.
An Overview of Esophageal Disorders in Children

Benjamin D. Gold, MD
Professor of Pediatrics and Microbiology Marcus Professor and Director Pediatric Gastroenterology, Hepatology and Nutrition Department of Pediatrics Emory University School of Medicine and Health Sciences Atlanta, GA
First, an overview of esophageal disorders in children.
Current Controversies in GERD and Esophageal Disease

Many acid suppression options are available, but we have limited promotility agents why? Acid versus nonacid what role does nonacid reflux play in the propagation of GERD? What is the role of inflammation in the esophagus?
What I would like to do is to start off with the controversies. These are the things that I think we still wrestle with on a day-to-day basis with the patients that we get referred to us from pediatricians. There are a whole lot of acid suppressing options that are available, with now 3 PPIs FDA approved for the pediatric population. We really have limited promotility agents. One of the questions I want you to think about is Why? Is this entity of nonacid reflux a true entity in terms of causing disease? So acid versus nonacid, and what roles does nonacid reflux play in the propagation or actually etiology of GERD? What is the role of inflammation in the esophagus? What does it mean? How many eosinophils make up eosinophilic esophagitis versus GERD versus some entity in between?
Overview of GERD
So first, an overview of GERD.
GERD as a Chronic Disease

Frequent: infants vs. older children High incidence1
0.91 incidence density from birth to age 5 years (per 1000 person-years)* 11% to 24% had 3 medical visits 11% to 20% had symptoms for more than a month
Has frequent relapses and requires prolonged treatment Childhood GERD probably persists into adulthood3-5
Treatment aimed to prevent mucosal damage, control symptoms, prevent complications, and treat atypical manifestations
* Presented for medical attention
DK, et al. Clin Gastroenterol Hepatol. 2007;5:186-191. 2Hassall E, et al. J Pediatr. 2007;150:262-267. 3El-Serag HB, et al. Am J Gastroenterol. 2004;99:806-812. 4Waring JP, et al. J Pediatr Gastroenterol Nutr. 2002;35:334-338. 5Young RJ, et al. Dig Dis Sci. 2007;52:457-462.
1Chitkara
Reflux-related diseaseand I do not need to tell you all thisis frequent in infants and in older children, and it seems to go up with increasing age. True populationbased incidence and prevalence studies have not necessarily been done, but there are a number of papers presented at this meeting that do provide some more recent data. GERD is a disease that in some is outgrown and in others can continue for their lifetime with periods of wellness and periods of symptomatology. I think an important area where research really needs to head are longitudinal studies. In particular, while having somebody of repute like Dr. Castell here from the adult side, how do we learn how to transition these patients once they hit adolescence into adults and are cared for by our adult colleagues? Finally, treatment aimed to prevent mucosal damage and control symptoms and prevent complications and treat atypical manifestations really is directed at the effector of the damage rather than the actual underlying cause.
GERD Pathophysiology: A Motility Disturbance Leading to Esophageal Damage

PRIMARY MECHANISM 1: Transient lower esophageal sphincter relaxation (TLESR); decreased lower esophageal sphincter (LES) pressure leads to reflux PRIMARY MECHANISM 2: Impaired esophageal clearance, acid sensitivity, inhibited peristalsis
Adapted from Jadcherla SR, et al. Am J Med. 2001;111(suppl 8A):64S-68S.
This slide here really highlights for you what is the overall pathophysiology. I think what is exciting standing before you tonight is that now there are some data in children. Sudarshan Jadcherla from Columbus Childrens is one of those that has really done some of the seminal work that has demonstrated that the exact same mechanisms in children with GERD as compared to those that are not are seen in adults with GERD as compared to those that are not. That is, primary mechanism being transient lower esophageal sphincter relaxations, which decrease at certain times and open inappropriately, and then secondarily, impaired esophageal clearance of acid refluxate. The same mechanisms in a 1-month-old with true GERD, a 5-year-old, a 15-year-old, or an almost 50-year-old with GERD are existing in patients with this entity. So, it is a motility-related disorder.
Audience Interaction
If GERD is a motility disorder, why do we have many acid suppression options, but so few promotility agents?
If it is a motility-related disorder, why are there so many acid suppressing agents that are available and are effective in the majority of patients with GERD, but so few promotility agents? So our first team question to address, and Drs. Nurko and Furuta are now rounding the audience, and since they know some of you, just beware you may be called upon. So discuss amongst yourselves for the next couple of minutes what you think the answer to this particular question might be. So again, GERD is a motility disorder, but the effector of the damage is acid, and why do we have so few promotility agents available? This is a team effort, so talk amongst yourselves. Dr. Furuta and Dr. Nurko, are you ready to ask a particular team? (Dr. Nurko) Yeah, I think we are ready. Here, we have a volunteer. (Dr. Gold) Dr. Colletti, it is so good to see you this evening. (Dr. Colletti) We have them but they dont work. (Dr. Gold) There is a good short answer. Do we have consensus here? Somebody else that wants to offer some other (Dr. Furuta) Dr. Teitelbaum has an answer here. (Dr. Teitelbaum) I think that is true that there is not a lot of evidence that the ones we have work but the other problem is that the ones that we at least hope would work have a lot of side effects related to them, and when you try to affect the GI nerves then you end up affecting the nerves of other organ systems, and then they get pulled from the market. (Dr. Gold) So, side effects, being pulled from the market, we have them but they do not work. One more response and then we need to move on. There are other medications such as baclofen that affect the lower esophageal sphincter, and that is a wonderful segue to where we are going to head next in the presentation because we will actually talk about that from both the pediatric and the adult perspective.
Overview of GERD Treatments

Nonpharmacologic
Infants Formula thickening Time-limited trial of hypoallergenic formula Higher calorie formulas Nasogastric/nasojejunal feeds Older children/adolescents Positioning/head-of-bed elevation Weight loss (if overweight)
Pharmacologic
Oral antacids Surface agents (eg, sodium alginate, sucralfate) Gastrointestinal prokinetic agents (eg, domperidone, baclofen) Acid-suppressive agents (H2RAs, PPIs)
Surgical
Fundoplication (ie, Nissen) Enteral feeding device Esophagogastric dissociation
Tipnis NA, et al. Curr Treat Options Gastroenterol. 2007;10:391-400.
This slideand for the sake of time I will not go through it for youhighlights some of the nonpharmacologic, pharmacologic, and surgical methodologies that are used. I think we would all agree, and that was in the first GERD guidelines published by our society and endorsed by the American Academy and the revised GERD guidelines, which should be published actually within the next year. I am told by a very reliable source, including the convener of those revised guidelines, that they are about three-quarters to 85% through. The bottom line is that we use the nonpharmacologic or conservative methodologies whether or not we use pharmacologic or surgical therapy. Once we have decided that the child or infant or adolescent does not respond we go to pharmacologic management, and then often times after they failed, we go to fundoplication. Actually, during the course of the presentation, particularly Drs. Nurko and Castell, you will hear some thoughts and data actually with respect to the role of fundoplication.
Pharmacotherapy Options for GERD

Therapy Considerations
Available for infants (limited data), children, and adults Evidence suggests poor clinical efficacy
Motility Agents
Metoclopramide
Side effects of anxiety, tremors, and dystonia

Bethanechol
Side effects (dizziness, vomiting, sweating, upset stomach) generally outweigh any benefit
Cisapride
Risk of cardiac arrhythmia No longer available

Domperidone
Not available without IND

Baclofen
Neurological side effects including drowsiness and weakness
Due to the lack of proven efficacy, side effects, and proven risks with all of these agents, individual clinician discretion is necessary when using these agents for treatment of GERD
Hassall E. J Pediatr. 2005;146(3 suppl):S3-S12. Physicians Desk Reference. Montvale, NJ. Thomson PDR; 2007. Tipnis NA, et al. Curr Treat Options Gastroenterol. 2007;10:391-400.
With respect to motility agents, the list of those that were players, are no longer players, are shown on this particular slide. As you can see with the top one, metoclopramide, actually being the number one drug that is prescribed by NICUs in a recent survey by the NICHD Neonatal Network that neonates are sent home on. In 6 randomized, placebo-controlled trials, not one except for that which used pHmetry, was there a clinically evident benefit from those medications. Bethanechol actually does have some potential use, and there is some data that will be presented by Dr. Castell, as well as domperidone. Baclofen actually does have some potential role, and it is an exciting area with respect to the motility-related field, particularly looking at GABA receptors and agents that might have some activity on that aspect of esophageal disease.
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Pharmacotherapy Options for GERD (cont.)

Therapy
Histamine2Receptor Antagonists (H2RAs)
Considerations
Available for infants (ranitidine), children, adolescents, and adults
Solution or suspension forms and effervescent tablet
Less potent acid suppression compared with PPIs Tachyphylaxis (ie, tolerance) is an issue
Lansoprazole and omeprazole available for children, adolescents, and adults Esomeprazole available for adolescents and adults Proton Pump Inhibitors (PPIs) Multiple formulations for ease of use Superior efficacy to H2RAs for healing and pH control Cost and managed care restrictions
Hassall E. J Pediatr. 2005;146(3 suppl):S3-S12. Physicians Desk Reference. Montvale, NJ. Thomson PDR; 2007. Tipnis NA, et al. Curr Treat Options Gastroenterol. 2007;10:391-400.
For sake of time again, I will not review for you the pathophysiology of acid secretion or physiology if you will and the H2 receptor antagonists and the proton pump inhibitors. Suffice it to say there are 4 H2 blockers that are approved for pediatric patients and 3 PPIs that are FDA approved, lansoprazole, esomeprazole, and omeprazole.
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What Role Does Nonacid Play in the Pathogenesis of GERD?
So what role does nonacid play in the pathogenesis of GERD? I think to set the stage for my 2 colleagues, which will go into this in more detail, a couple of definitions for you.
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Esophageal pH Levels Determine Type of Reflux

Refluxed gastric contents with a pH < 4 that can either reduce the pH within the esophagus to < 4 or occur when intraesophageal pH is already < 4 Reflux events that result in an esophageal pH level between 4 and 7 Reflux episodes during which the lowest esophageal pH level does not drop below 7
Acid reflux
Weakly acidic reflux Weakly alkaline reflux (nonacid)
Sifrim D, et al. Gut. 2004:53:1024-1031.
So acid reflux is reflux of gastric contents, with a pH less than 4 that can either reduce the pH within the esophagus to less than 4 or occur when intraesophageal pH is already less than 4. Weakly acid reflux, which is also termed nonacid reflux, occurs when the esophageal pH is between 4 and 7, and then weakly alkaline reflux or true nonacid reflux is when the pH does not drop below 7.
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Agents Targeting Lower Esophageal Sphincter Relaxations

Decrease LES Relaxation Baclofen Morphine Ondansetron Atropine Somatostatin Increase LES Relaxation Cholecystokinin-A Nitric Oxide Sumatriptan
Side effects or lack of efficacy hamper further development or use in clinical practice of most of these agents In healthy adults and in adults with GERD, baclofen has been shown to reduce acid and nonacid reflux Baclofen is known to cause dyspeptic symptoms, drowsiness, dizziness, fatigue, and to lower threshold for seizures
Di Lorenzo C. J Pediatr. 2006;149:436-438.
Now there are a number of agents that target the lower esophageal sphincter relaxations. Shown on this slide are a list of those agents that either decrease LES relaxationso a medication, like that last comment, baclofen, ondansetron, atropine, somatostatinor those that increase LES relaxation, such as cholecystokinin or nitric oxide. I think it is a very exciting area in which a lot of research is now ongoing in clinical trials.
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Efficacy of Baclofen in Children by Accelerating Gastric Emptying*
Placebo Group Gastric Emptying

Session I (received baclofen) 61 (39, 81) 56 (48, 73) Session 2 (received placebo) 114 (67, 170) 86 (70, 108)
Baclofen Group
Session 1 (received baclofen) 71 (33, 95) 66 (51, 91) (P = 0.077) 3.3 0.1 Session 2 (received baclofen) 61 (47, 84) 68 (56, 77)
Gastric Emptying t (min) Gastric Emptying tmax (min) Gastric Emptying Coefficient
3.3 0.1
2.8 0.2
3.2 0.2
* Randomized, double-blind, placebo-controlled trial N = 30 (18 male, 12 female; mean age 10.0 0.8 years) P < 0.05
Omari TI, et al. J Pediatr. 2006;149:468-474.
With respect to gastric emptying, this is a particular study. Now I am going to focus on the gastric side of it, and then Drs. Castell and Nurko will talk about the esophageal side. This is a particular study that looked at baclofen to accelerate gastric emptying, and as you can see this was actually a randomized, double-blind, placebo-controlled trial in children. The cohort size was 30. You will see the breakdown, 18 male, 12 female, and the median age was about 10 years of age. There was the placebo group, and they had 2 sessions, and then a baclofen group. The bottom line was that this medication actually did accelerate gastric emptying, whether it was looking at a time for gastric emptying or gastric emptying coefficient.
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Overview of Esophageal Diseases in Children
A potpourri if you will of esophageal diseases in the next few minutes I am going to do for you and then lead into our discussions in more detail on acid versus nonacid reflux in eosinophilic esophagitis.
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Audience Question
Common presenting symptoms of an esophageal motor disorder include?
1. 2. 3. 4. 5. Waterbrash Dysphagia Regurgitation Odynophagia All of the above
The first audience response question, so take your keypads now. The question is as follows. Common presenting symptoms of an esophageal motor disorder include? You have 5 choices: 1. Waterbrash 2. Dysphagia 3. Regurgitation 4. Odynophagia 5. All of the above
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Audience Question Results

Common presenting symptoms of an esophageal motor disorder include?
Waterbrash Dysphagia Regurgitation Odynophagia All of the above
2% 7% 5% 4% 82%
The audience says 2% waterbrash, 7% dysphagia, 5% regurgitation, 82% all of the above. Very good. The audience is very clued in to what we have here, and I am not going to further discuss the answers. Next slide please.
Esophageal Motor Dysfunction

Primary Motor Disorder: usually affects the esophagus alone and often has no known etiology
Examples: nutcracker esophagus, diffuse esophageal spasm, achalasia
Secondary Motor Disorder: motility dysfunction caused by a systemic or local condition

Examples: esophageal atresia/tracheoesophageal fistula, Crohns esophagitis
Common presenting symptoms of esophageal motor disorders:

Dysphagia Nonheartburn chest pain Bleeding Regurgitation Heartburn/pyrosis Waterbrash Respiratory/laryngeal symptoms Odynophagia
Paterson WG, Mayrand S. The esophagus. In: Thomson ABR, Shaffer EA, eds. First Principles of Gastroenterology: The Basis of Disease and an Approach to Management. 3rd ed. Ottawa: Canadian Public Health Association; 1997:88-128. Gold B. Other neuromuscular disorders. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. In press.
So first, with respect to esophageal motor disorders, they are broken down into primary and secondary, and the definitions are shown on this slide. Primary motor disorders of the esophagus usually affect the esophagus alone and often have no known etiology. Examples are diffuse esophageal spasm and achalasia. Secondary motor disorders are motility dysfunction that is caused by something else, either a systemic or a local condition. Examples are shown there, and they actually can be things like esophageal atresia and tracheoesophageal fistula, Crohns disease, or even eosinophilic esophagitis. Common presenting symptoms as you all correctlyor at least 82% of you chose are shown in the list in this slide ranging from dysphagia to waterbrash to odynophagia and even respiratory and laryngeal symptoms.
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Primary Esophageal Motility Disorders

Disorder Characteristics
Absence of peristalsis in smooth muscle component of esophagus Elevated intraesophageal baseline pressure (versus gastric baseline) Achalasia Incomplete LES relaxation Elevated LES pressure Simultaneous contraction in smooth muscle portion of esophagus Diffuse Esophageal Spasm (DES) Periods of normal peristalsis Occasional spontaneous/repetitive contractions Prolonged duration of some contractions (> 6 seconds) Nonspecific Motility Disorder (Ineffective Esophageal Motility) Abnormal peristalsis not meeting criteria for other motor disorders Reduced amplitude (ineffective esophageal peristalsis) < 30 mm Hg Triple peaked contraction waves Prolonged/spontaneous/simultaneous contractions
Arora AS, et al. Curr Gastroenterol Rep. 2001;3:191-199.
Primary motor disorders, and the next 2 slides are going to focus on these, are grouped into the following: achalasia, where it is characteristic of primary achalasia, and then secondary, which can be caused by an infectious agent, absence of peristalsis in the smooth muscle component of the esophagus, and elevation consistent of intraesophageal baseline pressure and incomplete LES relaxation; diffuse esophageal spasm; and then what used to be called nonspecific motility disorder but now actuallyand you will see some data in more detail in Dr. Nurkos and Dr. Castells talkineffective esophageal motility.
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Secondary Esophageal Motility Disorders

Disorder
Esophageal Atresia/ Tracheoesophageal Fistula
Characteristics
Abnormal peristalsis Impaired LES function Simultaneous and repetitive low-amplitude esophageal contractions Signs of intestinal obstruction without evidence of mechanical blockage Aperistalsis Decreased or absent LES with failure of LES to relax with swallowing Strictures of esophagus and dysphagia in subacute and chronic stages Normal UES and LES function
Chronic Idiopathic Intestinal PseudoObstruction
Caustic Ingestion
Gold B. Other neuromuscular disorders. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. In press.
In terms of secondary esophageal motility disorders, esophageal atresia or tracheoesophageal fistula, abnormal peristalsis and impaired LES function, and in fact in longitudinal studies there have been 3 papers published just in this past year, which actually looked at the incidence or prevalence if you will, because it is cross section, of Barretts esophagus and even adenocarcinoma in these patients. We have absolutely no guidelines, at least as pediatric gastroenterologists, in how to perform ongoing surveillance of these particular children and whether or not they merit being on a PPI or some other medication for life. Chronic idiopathic intestinal pseudo-obstruction, which tends to primarily occur in the midgut and colon, can also affect the esophagus, and then caustic ingestion, something which happens in 10%20% of children in the United States, at least based on 2000 CDC data, can also cause a secondary motility disorder.
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Secondary Esophageal Motility Disorders (cont.)

Disorder
Eosinophilic Esophagitis
Characteristics
Linear shearing of esophageal body Excessive eosinophils in esophageal mucosa Esophagrams either normal or demonstrate a static narrowed caliber Transmural inflammation that can occur in any part of digestive tract Manometry findings similar to achalasia hypertensive lower esophageal sphincter but inconsistent findings concerning peristalsis and sphincter relaxation
Esophageal Crohns Disease
Gold B. Other neuromuscular disorders. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. In press.
Eosinophilic esophagitis, which we will talk about in much more detail in Dr. Furutas section, can also cause a motility disorder, and then esophageal Crohns disease.
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Other Esophageal Disorders in Children
Other esophageal disorders that you have to consider in terms of motor disorders
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Differential Diagnosis
Infectious esophagitis Complications of bone marrow transplants Crohns esophagitis Foreign body Congenital malformations Eosinophilic esophagitis
Paterson WG, Mayrand S. The esophagus. In: Thomson ABR, Shaffer EA, eds. First Principles of Gastroenterology: The Basis of Disease and an Approach to Management. 3rd ed. Ottawa: Canadian Public Health Association; 1997:110-111..
and the differential would be an infectious esophagitis and complications of bone marrow transplants, which we are seeing a lot more, particularly at hospitals that have busy BMT services. Crohns esophagitis, foreign bodies, caustic ingestions, congenital malformations, and then eosinophilic esophagitis. Then to transition into that, I think this is at least one of those who I would say I am a helicophile being an interest in H. pylori over the last 20 years, this is the H. pylori of the 2000s.
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Eosinophilic Esophagitis Can Mimic GERD

Allergic esophagus is the prevalence of this disease or physician awareness increasing? Prevalence estimates
3.4% of children with reflux symptoms 6.8% of children with esophagitis 20% of children with dysphagia
Signs/symptoms
Dysphagia, food impaction, heartburn, abdominal/chest pain, vomiting, regurgitation, odynophagia, feeding refusal
Distinguishing primary histologic feature: striking eosinophilia of the esophageal mucosa (often with eosinophil microabscesses) Clinical characteristics
Male predominance (70%-80% of cases) Family or personal history of allergy/atopy
Asthma, rhinitis, eczema, food allergy Furuta GT, et al. Gastroenterology. 2007;133:1342-1363. Arora AS, et al. Clin Gastroenterol Hepatol. 2004;2:523-530.
The attention on eosinophilic disorders and in fact what it has done in terms of understanding the role or maybe pointing clues to how much we do not understand as far as the role of inflammation in the esophagus and that the etiologies behind it, whether it is aeroallergens, whether it is ingested food allergens or both, I think is an important issue. Again, population-based studies have not been done but clearly in single-center studies, the overall prevalence seems to be increasing as is the numbers of papers published in parallel. So prevalence estimates range from 3.4% of children with reflux-related symptoms, almost 7% of children with esophagitis, and 20% of children with dysphagia. Signs and symptoms can range from dysphagia, food impaction, abdominal and chest pain, vomiting, and feeding refusal. Distinguishing primary histologic features such as What is the appropriate number of eosinophils per high-powered field as it relates to this disorder? I think is an important one. Clinical features, as in many of the esophageal disorders, the Y chromosome is the weaker link. Male predominance 70% to 80% of cases, and there is often a family or personal history of atopy and allergy.
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Eosinophilic Esophagitis Can Mimic GERD

Allergic esophagus is the prevalence of this disease or physician awareness increasing? Prevalence estimates
3.4% of children with reflux symptoms 6.8% of children with esophagitis 20% of children with dysphagia
Consider eosinophilic esophagitis when GERD symptoms not responding to PPIs
Signs/symptoms
Dysphagia, food impaction, heartburn, abdominal/chest pain, vomiting, regurgitation, odynophagia, feeding refusal
Distinguishing primary histologic feature: striking eosinophilia of the esophageal mucosa (often with eosinophil microabscesses) Clinical characteristics
Male predominance (70%-80% of cases) Family or personal history of allergy/atopy
Asthma, rhinitis, eczema, food allergy Furuta GT, et al. Gastroenterology. 2007;133:1342-1363. Arora AS, et al. Clin Gastroenterol Hepatol. 2004;2:523-530.
So consider esophagitis when GERD symptoms are not responding to PPIs, and you will see how that fits nicely in the next 2 talks.
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Summary
Esophageal disease presents in many forms (eg, motor dysfunction; infectious esophagitis; Crohns esophagitis; eosinophilic esophagitis) GERD is a motility disturbance; yet there is a shortage of treatment options for transient lower esophageal sphincter relaxation
Therapy targets the effector of the esophageal and extraesophageal inflammation
Most GERD responds to acid suppression What do you do when patients are not responding to acid suppression therapy?
To summarize now, with 1 second left and we will move over to our next 2 presentations, esophageal disease presents in many forms ranging from motor dysfunction, primary or secondary, infectious esophagitis, Crohns disease, and eosinophilic esophagitis. GERD is a motility-related disorder where the effector of the damage is acid, and yet there is a shortage of treatment options available with efficacy that affect LES function and esophageal body peristalsis. Therapy is therefore targeted against the effector of the esophageal and extraesophageal inflammation. Most GERD responds to acid suppression. We have good agents that are on the market that can heal symptoms, that can heal the mucosa, and that can keep people in remission from pediatric patients with simple nonerosive esophagitis with erosive esophagitis to adults with Barretts esophagus. But, what do you do when patients are not responding to acid suppression therapy and come into your office? We are going to talk a lot about this in the next few presentations.
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The Role of Nonacid and Acid Reflux in GERD

The Pediatric Perspective
Samuel Nurko, MD, MPH

Associate Professor of Pediatrics Harvard Medical School Director, Center for Motility and Functional Gastrointestinal Disorders Childrens Hospital Boston Boston, MA
(Dr. Gold) Now I am going to turn it over to Dr. Samuel Nurko, who is going to talk about the role of nonacid and acid reflux in GERD from the pediatric perspective. (Dr. Nurko) Thank you Ben. I want to thank the organizers for allowing me to participate. I appreciate that you have had a very long day. I appreciate you being here. I hope it is not only for the dinner. My task was to really focus on the role that nonacid and acid reflux play in GERD in children. I am going to give you the pediatric perspective.
Role of Acid in Pediatrics

35
Percent of total time pH < 4
30 25 20 15 10 5 0
Controls
Mild to moderate esophagitis
Severe esophagitis
Orel R, et al. J Pediatr Gastroenterol Nutr. 2003;36:266-273.
I think as Ben was mentioning and just to start from a plain field, we all know that the role of acid in pediatrics has also been detrimental, and this is one of the studies that was published a few years ago where you can see that as you increase the percent of total time with a pH less than 4 in your esophagus, your severity of esophagitis tends to increase. We have evidence that increased acid in the esophagus gives you increased inflammation.
Effect of Omeprazole on Children With Erosive Esophagitis

N = 65 children aged 1-16 years with erosive esophagitis
Series 1
100 95 72
Percent of patients
80 60 44 40 20 0 Healed with 0.7 mg/kg/day
Healed with 1.4 mg/kg/day
Healed with 3.5 mg/kg/day
Hassall E, et al. J Pediatr. 2000;137:800-807.
We also know that if you take away the acid, this esophagitis tends to heal, and this you can see as studied from Eric (Hassall) a few years ago, where you can see how the esophagitis heals, and it heals much better with a higher dose of PPI.
Effect of Omeprazole on Symptoms in Children With Esophagitis

100 80 60 40 20 0
Overall Heartburn Dysphagia Irritability Coughing
Percent of patients with moderate to severe symptoms
Pre-entry 5-14 days 3 months

N = 54
Hassall E, et al. J Pediatr. 2000;137:800-807.
What about symptoms? There are studies with different PPIs. This is the same study from Eric (Hassall) in which you can see how the symptoms decrease over time, 5-14 days in yellow, 3 months in red, and you can see when you take patients that have GERD and evidence of esophagitis and you give them an acid suppressing agent, the symptoms really decrease. This has been replicated with other PPIs.
Effect of Lansoprazole on GERD Symptoms in Children

100 90
91
85
Nonerosive, 15 mg once daily (n = 64) Esophagitis, 30 mg once daily (n = 23)

P < 0.001 vs. pretreatment 51 43 43
Median days with GERD symptoms (%)
80 70 60 50 40 30 20 10 0
18
16
16
Pretreatment
4 weeks
8 weeks
Final visit
Fiedorek S, et al. J Pediatr Gastroenterol Nutr. 2005;40:319-327.
This is a study with lansoprazole. You can see very similar effect and actually even in atypical symptoms.
Efficacy of Lansoprazole on Extraesophageal Symptoms in GERD

66 children aged 1-11 years treated with lansoprazole 15 or 30 mg QD or 30 mg BID for 8 to 12 weeks
100 90 80 70 60 50 40 30 20 10 0
Percent of children with improvement in symptoms
79* 63
81*
Cough
Wheeze
Hoarseness
* Statistically significant change in symptom severity from baseline to final visit based on sign test at P 0.001 Tolia V, et al. J Pediatr Gastroenterol Nutr. 2002; 35(suppl 4):S308-S318.
You can see that atypical symptoms associated with reflux also respond to gastric acid suppression. So I think that what we know is that when acid production is blocked or neutralized with the use of medications, the symptoms improve and the esophagitis heals. We also know that this response to acid suppression medication indicates that acid definitely plays a role in GERD.
Does Acid Explain Everything?

When gastric acid production is blocked or neutralized with the use of medication:
Symptoms improve Esophagitis heals
Response to acid-suppressive medication indicates role acid plays in the pathogenesis of GERD However:
Some patients continue with symptoms despite aggressive medical therapy Some patients do not respond to acid suppression therapy, have normal pH probes, and experience dramatic improvement in their symptoms after fundoplication
Are we missing something?
However, as all of us know, and maybe that is the reason you are here, many patients continue with symptoms despite aggressive medical therapy, and some people that do not respond to acid suppression therapy have actually normal pH probes by the best standards we have and experience dramatic improvement in their symptoms after fundoplication. This begs the question: are we missing something? What else could be going on? Is the tool to decide if we have enough GERD the wrong tool? Is the pH probe not good enough? Or are we missing something different?
Audience Question
I utilize the following test most often for children with persistent GERD symptoms who are unresponsive to acid suppression treatment:
1. 2. 3. 4. Endoscopy pH monitoring Wireless pH monitoring Multichannel intraluminal impedance
So this is another audience question that Im going to pose to you. I utilize the following test most often for children with persistent GERD symptoms who are unresponsive to acid suppression treatment: 1. Endoscopy 2. pH monitoring 3. Wireless pH monitoring or BRAVO 4. MII, or multichannel intraluminal impedance Again, there is no right or wrong answer.

I utilize the following test most often for children with persistent GERD symptoms who are unresponsive to acid suppression treatment:
Endoscopy
65%
pH monitoring
15%
Wireless pH monitoring Multichannel intraluminal impedance
2%
18%
This is an interesting response actually. Most people in the audience, 65%, would do endoscopy, and I suspect that is because you want to exclude the presence of eosinophilic esophagitis. I just want to press upon the fact that probably Glenn is going to touch on that. It is very important to do this after the patients have had a very good PPI treatment. The pH monitoring, as we are going to talk about later, has limitations, and if you are not completely blocked, it can be useful, but if you are completely blocked, the pH monitoring is going to miss every reflux that is not acid. Wireless pH monitoring is a new technique. It is good because you can do it for 3 or 4 days so it has advantages. Most people do it for 2 days. You can do it with and without treatment and have some advantages. Finally, I think impedance is one of the techniques that is being used more. I am going to try to put these techniques in perspective during the talk today.
Limitations of pH Monitoring
Lack of sensitivity and specificity
Reduced patient physical and dietary activity Variability in acid exposure Electrode positioning and displacement
Are symptoms/problems related to nonacid reflux?

Other components of gastric refluxate (bile, pepsin)?
To address the limitations:

Wireless pH monitoring Impedance monitoring and pH Other methods
Kahrilas PJ, et al. Aliment Pharmacol Ther. 2005:22(suppl 3):2-9.
What are the limitations of pH monitoring? We clearly lack there is a lack of sensitivity and specificity that is very well described, and I am not going to dwell too much on it, but we know that this is related to reduced patients physical and dietary activity. Most of the kids we do the pH probe on do not go to school and do not do sports. You have variability in acid exposure, so depending on where your catheter is and how it is facing, electron positioning is a problem, and in pediatrics we never know exactly where we are. Most of us do not do manometry, and we either use the total formula or we use the NASPGHAN criteria, but there is also displacement, and all of us have cases in which you can actually see during the study how the pH probe has migrated into the stomach or into a hiatal hernia. Now, the question, not everything is acid exposure. We also have what is called relation to symptoms, and are the symptoms we are facing in the problems related to acid or nonacid reflux? There may be other components that are not actually acid that make reflux be an important entity.
10
BRAVO pH Monitoring
Miniature pH capsule (size of gelcap) is attached to esophagus1
Capsule measures pH in esophagus and transmits information to a pager-sized receiver worn on belt or waistband Test lasts 24 to 48 hours Test data are uploaded to a computer and analyzed Capsule positioned in esophagus1
Advantages for use in children2:

Prolonged studies, high satisfaction rate Does not require nasogastric tube to be placed Less interference in daily activities Better tolerated
Possible disadvantages for use:

Age limitation Invasive Capsule recording pH and sending data to transmitter1 Cost
1Reprinted from Medtronics Web site. http://www.medtronictreatssca.net/neuro/gerd/bravopatient_final.pdf. Accessed October 15, 2007. 2Senders CW. Curr Opin Otolaryngol Head Neck Surg. 2006;14:38-40.
To address these 2 limitations of the probe, different advances have been obtained. One is obviously the wireless pH monitoring or BRAVO, and the other one is the way to look for nonacid reflux. So, BRAVO monitoring has taken off in pediatrics. There are more and more centers. I recently did a nonacademic survey, and there were like 15 centers using it from the ones that responded to me. I am sure there are many more that are using it. As you can see, it is a miniature pH capsule that gets hooked by suctioning the tissue. This actually allows you to have nothing in the nose, and the patients can have their normal activity. There big advantages in children are this allows you to do prolonged studies, and there is a very high satisfaction rate, both in adults and children. It does not require the nasogastric tube placement. There is much less interference. We have patients that can actually do track or do whatever exercises they are doing. In general, comparison studies in adults, because there are none in children, suggest that it is much better tolerated. What are the disadvantages for its use in pediatrics? The big one is the age limitation. Even though there are reports of people doing BRAVO monitoring even in kids of 5 or 4 years of age, I think most of us are reluctant to do it in kids that are so young just because of the fear of perforation. It is more invasive. You need an endoscopy usually to be able to place it. Finally, is the cost, each capsule is quite expensive.
11
Tolerability and Reliability of Wireless pH Monitoring in Children

44 children (27 males, 17 females)
Mean age 11.8 years with 48-hour testing
Data analysis revealed that the overall reproducibility of a single 24-hour period was 77%
Reproducible: if the index was normal (pH < 4 for less than 5%) or abnormal on both study days
No significant difference between the 2 days (P = 0.11)

Ten of 44 patients had conflicting results on day 1 compared with results on day 2
Majority (68%) of patients reported some degree of discomfort during the study
Pain was generally mild
Hochman JA, et al. J Pediatr Gastroenterol Nutr. 2005:41:411-415.
What is the evidence in children? There is only 1 published paper so far that had shown that the BRAVO monitoring was used in 44 children. You can see the age here. The data analysis was very good. It revealed that the overall reproducibility of a single 24-hour period was 77%. What this shows you is that if you compare the first day with the second day, it is not 100%, but it was close to 80%. There was no significant difference between the 2 days when you were trying to compare both. The authors erred on the side that if there was conflicting evidence they always erred on the side of diagnosing reflux. What they did have, however, is that most of the patients, 68%, reported some degree of discomfort during the study. The pain was really generally mild, but there was also a sensation of a foreign body. We do not know how this is going to compare with other techniques we do, but in adults all of the surveys constantly show that adults prefer to have the BRAVO versus something in their nose.
12
Measuring Reflux by Multichannel Intraluminal Impedance

Detects both acid and nonacid reflux
Acid reflux = drop in pH below 4.0 Nonacid reflux
Electrical impedance changes when a bolus of fluid or air passes between electrical sensors along a catheter Allows evaluation of the nature and pH of refluxate and proximal extent of a reflux event Determines characteristics of reflux
Gas Liquid Gas and liquid
Vela MF, et al. Gastroenterology. 2001;120:1599-1606. Sifrim D, et al. Gastroenterology. 2001;120:1588-1598. Tipnis NA, et al. Curr Treat Options Gastroenterol. 2007;10:391-400.
Now, the problem with the BRAVO and the pH probe is it does not address the fact that not all reflux is acid. The advantage in the advent of the impedance or MII is that it can detect both acid and nonacid reflux. Ben already showed you the definitions. You have acid reflux when you drop below 4 and nonacid reflux when it is above 4. You can have weakly acidic within the nonacid reflux, which is to 4 to 7, or alkaline reflux. How does impedance work? Impedance is measuring electrical resistance between electrodes. Given that it is not pH dependent, it is flow dependent, so it allows you the evaluation of the nature of the refluxate that you have. You can see if you have liquids, if you have gas, if you have mixed reflux. It always is done with an attachment of a pH meter, so it allows you to decide if you are having reflux if the reflux is acid or nonacid; that is why the technique is combined.
13
Impedance Wave
Air preceding bolus Liquid bolus Recovery
Ohms
Based on changes in resistance to electrical current
Time
Wise JL, et al. Dis Esoph. 2007;20:83-88.
This is just a schematic example, and Don is going to show you more information of these. You have the electrodes, where you are measuring the electrical resistance. You have a pH that does not show very well that is measuring the reflux. The impedance changes with the different substances you have in your esophagus. Air has very high resistance. If air goes through the 2 electrodes, you can see there is a big upward curve. Liquids have decreased resistance, so you can see how the impedance changes. If you use things like saline or things with electrolytes, the drop is even more. Eventually, it recovers.
Impedance Wave
Air preceding bolus Liquid bolus Recovery
Ohms
Based on changes in resistance to electrical current
Time
Time
Time
Wise JL, et al. Dis Esoph. 2007;20:83-88.
So, by doing this, if you have a series of electrodes at different parts, the resistance between each one of the pairs is going to be measured, and then you can see that depending on what is happening you are going to see impedance changes. So, if you are swallowing something, the impedance is going to decrease, and it is going to start from the upper electrodes to the lower electrodes, and you will see this pattern, in which you can imagine how the reflux is occurring and how the swallowing is occurring, the bolus is going down. On the other hand, if the liquid is going from the stomach up into the mouth, it happens backwards, you can see how it starts distally at this level and it goes up to the mouth.
Representative Impedance Tracing: Nonacid Reflux Episode
Nonacid, full column
Impedance
reflux episode
Height
Bolus clearance time (BCT)
pH
Image courtesy of Samuel Nurko, MD, MPH.
This is how a real impedance tracing looks. We do not have time to really go into much, but you can measure 6 channels. You can see the height of the reflux; you can see here is a reflux episode that is going retrograde; and you can actually measure the pH. This would be a typical nonacid reflux episode that would not be detected by a pH probe. This is the advantage of the impedance. It allows you to see how high it goes; allows you to see what you have there, liquid, gas, or mixed; and allows you to decide if the reflux you are having is actually acid or nonacid.
16
Nonacid Reflux in Pediatrics

Nonacid reflux episodes recorded by impedance in 14 investigations involving children
Sifrim (n = 22) Rosen (n = 28) Mousa (n = 25) Wenzl (n = 22) Del Buono (n = 20) Corvaglia (n = 5) Wenzl (n = 14) Condino (n = 24) Condino (n = 34) Lopez-Alonso (n = 21) Lopez-Alonso (n = 7) Del Buono (n = 16) Mattioli ( > 1 yr) (n = 50) Mattioli ( < 1 yr) (n = 50) 40 45 49 89 69 78 55 51 53 73 46 56 49 53
20
40
60
80
100
Percent of nonacid reflux episodes recorded (relative to total number of reflux episodes recorded)
Vandenplas Y, et al. Acta Paediatr. 2007;96:956-962.
I am not going to have time to go through this slide. This is a recent report by Yvan Vandenplas. These are all of the studies in pediatrics that have been published up to early 2007. You can see that the prevalence of nonacid reflux varies from 40% to 80% depending on the age of the patients. We know that infants tend to have much more nonacid reflux.
17
Comparison of Impedance in Prematures and Adults

Adults
Total 24 hours Median 25th, 75th 95th Percentile
All Reflux
Total 30 18, 45 73 Duration(s) 10 6, 16 44
Frequency of Reflux Types

Acid 18 7, 31 55 Weakly acid 9 6, 15 26 Nonacid 0 0, 0 1 Superimp acid 0 0, 1 4 % Bolus exposure 0.5 0.3, 0.9 1.4 pH-only REs 0 0, 1 3
pH
% Acid exposure 1.2 0.3, 2.5 6.3
Shay S, et al. Am J Gastroenterol. 2004;99:1037-1043. Lopez-Alonso M, et al. Pediatrics. 2006;118:e299-e308.
How do nonacid reflux events in children compare to adults? We have no data. We do know this is the normal data from Shay, and Dr. Castell was part of this, where you can see the normal events of reflux.

Adults
All Reflux
Total 30 18, 45 73 Duration(s) 10 6, 16 44

pH
% Acid exposure 1.2 0.3, 2.5 6.3
Prematures
Median 95th percentile
Total reflux n / 24 hours 71 100.7
% Acid reflux 25.4 52.3
Weakly acidic (%) 72.9 98
Reflux-related acid exposure % / 24 hours 1.66 6.36
Total acid exposure % / 24 hours 5.59 20.17
This is the only study we have in kids. This is done in premature babies with an NG tube from Lopez-Alonso in Spain. The only thing I want to point out, of course these are preemie babies, they tend to have much more reflux episodes than adults; the reflux tends to be much more full column than in adults; and they tend to have much more nonacid reflux, which is related to the fact that the younger you are the more feedings you get in your stomach more frequently.

Adults
All Reflux
Total 30 18, 45 73 Duration(s) 10 6, 16 44

pH
% Acid exposure 1.2 0.3, 2.5 6.3
Full column 36%
Full column 90%

Total reflux n / 24 hours 71 100.7 % Acid reflux 25.4 52.3 Weakly acidic (%) 72.9 98 Reflux-related acid exposure % / 24 hours 1.66 6.36 Total acid exposure % / 24 hours 5.59 20.17
Prematures
Median 95th percentile
So, clearly, in between lies the rest of children, and we do not know what the normal values are, which brings me to the next point. Impedance cannot be used at this point to decide who is normal and abnormal. We do not have this standard. Impedance, however, can be used to try to explain if the symptoms you see in the PPI-resistant patient are related to reflux or not, and that is one of the most important messages I would like to leave with you.
Nonacid Reflux and Symptom Association

Multivariate analysis to determine which variable predicted symptom association with reflux
Predictor
Age Nonacid reflux Liquid reflux Proximal esophageal reflux Bolus clearance time
80 Acid reflux Nonacid reflux
58.8 75.3
Percent of reflux episodes
70 60 50 40 30 20 10 0 Distal Mid Proximal

5.4 2.9 19.4 8.8
Odds Ratio
0.88 (0.79-0.97) 1.70 (1.03-2.82) 0.63 (0.42-0.92) 1.31 (1.01-1.69)
P Value
0.01 0.04 0.02 0.04
1.00 (0.98-1.00)
0.36
Area of Esophagus
Rosen R, et al. Am J Gastroenterol. 2004;99:2452-2458.
This is our own study. As you can see, there was a good correlation between nonacid reflux, particularly if it was very high, and respiratory symptoms, as compared to acid reflux. So, clearly, nonacid reflux is important in the association of symptoms with patients that are resistant to therapy. This is just multivariate analysis to show you the same. Nonacid reflux, liquid reflux, proximal height, and the presence of nonacid reflux was most significant. How long the reflux was in the esophagus was not significant.
21
Is Impedance the New Gold Standard in Children?
So, I am going to pose the question to you: do we think that impedance is the new gold standard in kids?
22
Sensitivity of MII Versus pH Probe in Evaluation of Pediatric GERD Patients

pH Probe
Mean sensitivity in untreated patients (n = 25) Mean sensitivity in treated patients (n = 25) 80.6% 18.2%
MII
76.1% 13.5%
P value
0.41
47.2% 36.0%
80.3% 21.1%
0.005
Sensitivity of pH Probe (P = 0.10)

Infant (aged 0-2 years) Pediatric (aged 2-10 years) Adult (aged > 10 years) 49.9% 31.9% 63.2% 31.3% 77.1% 33.2%
Sensitivity of Impedance (P = 0.29)

80.4% 17.3% 80.8% 11.1% 71.8% 25.5%
Rosen R, et al. Clin Gastroenterol Hepatol. 2006;4:167-172.
That is a very difficult question. This is our own data trying to compare patients with impedance and pH probe, trying to analyze the sensitivity and specificity of both techniques. I do not have time to go through this, but I can tell you that in patients that are not being treated the sensitivity of the pH probe and the impedance was the same. In patients that you do tests on treatment, obviously because you are detecting more nonacid reflux, the sensitivity of the impedance is much higher, particularly if you have symptoms. However, if you look at age, you can see that in infants the sensitivity of the pH probe in untreated patients was much lower than the impedance. Again, this has to do with the way we feed infants. So, we can conclude that in the younger children impedance is probably better than a pH probe in an untreated patient, but as you go from school-age to older kids there does not seem to be any difference in the sensitivity of the test. Yes, you have more reflux, but the question is does that mean that that is important?
23
When Do You Use Impedance?

To study children that have not responded to medical treatment for GERD To try to establish if persistent symptoms on acid-suppressive therapy are related to reflux To evaluate patients that are continuously fed
So, when do we use impedance? I think it should be used to study children that have not responded to medical therapy to try to establish most importantly the symptoms on acid suppressive therapy as related to reflux. Obviously, we have a lot of patients that are continuously fed, and that is a perfect indication for impedance.
24
Audience Question
What are possible limitations/disadvantages of intraluminal impedance?
1. 2. 3. 4. 5. Lack of sensitivity and specificity Length of interpretation time Undefined normal values in pediatric patients 2 and 3 All of the above
So, that is another audience question at this point. What are possible limitations/disadvantages of intraluminal impedance? 1. Lack of sensitivity and specificity 2. Length of interpretation time 3. Undefined normal values in pediatric patients 4. 2 and 3 5. All of the above Some of these are to see if you really paid attention to what I said before, but some things are new.
25

What are possible limitations/disadvantages of intraluminal impedance?
Lack of sensitivity and specificity Length of interpretation time Undefined normal values in pediatric patients 2 and 3 All of the above
2% 1% 16% 48% 33%
Sensitivity and specificity is probably high. It is very good actually, and to detect reflux it is much better than anything else. The length of interpretation time in my experience is one of the biggest limitations of impedance. For all of us who do impedance, it takes a long time. The software has improved remarkably. There are different vendors. Actually, most of the vendors have actually improved the detection of reflux and the time has really decreased, but still it is not like a pH probe tracing that you just get a report and you sign off. You really need to go back to your tracing and be sure that what you are detecting is correct. There is still a time commitment. There is a learning curve. The undefined normal values clearly, as I mentioned before, is one of the biggest limitations to decide if the test is normal or abnormal; so we can only use it for symptom association.
Expert Opinion: Limitations of Impedance

In children it is not yet useful to determine if there is a pathologic amount of reflux Normal values are needed Other limitations include:
Length of time to interpret Similar to pH monitoring, proving causality is difficult
So, this is my expert Nurko opinion. We can discuss about this. I think that at this point impedance is not yet useful to determine if there is pathological amounts of reflux. Normal values are needed, and the other limitation, as I mentioned before, is the length of time, and again the fact that you have reflux and symptoms does not mean they are casually related. This is a problem that we deal with all of the time. Most of us use windows of 5 minutes, or you can use 2 minutes. So, it is very hard to demonstrate if the reflux is really occurring after the symptom or before the symptom. There are new advances in the way we are studying this. So, always remember that even with a positive association you have to go back and think.
27
Expert Opinion: Limitations of Impedance

In children it is not yet useful to determine if there is a pathologic amount of reflux Normal values are needed Other limitations include:
Length of time to interpret Similar to pH monitoring, proving causality is difficult
Pediatric studies are needed to determine if knowing the amount of nonacid reflux changes treatment or outcome
So, clearly we know that we need pediatric studies to know also if the amount of nonacid reflux changes the outcome and treatment. We are doing some studies on this, and the data is going to come, but that is the main question. If you do an impedance versus a pH probe or something else, do you really change the outcome of the patient by knowing the patient has more nonacid reflux?
28
Treatment of Nonacid Reflux
Surgery
What are the treatments? There are 3 modalities: Surgery. You know that is the best treatment.
29
Surgery
Medications
You have medications that already were alluded to.
30
Surgery
Medications
Other (jejunal feedings)
You can bypass the stomach and do something like jejunal feedings.
31
Fundoplication
16/17 patients with positive symptom index during MII improved after fundoplication 1/17 continued with symptoms Persistent symptoms in the patient with negative symptom index
Laparoscopic Nissen Fundoplication: Gastric fundus is wrapped around the lower esophageal sphincter to reinforce antireflux barrier, thus preventing the reflux of gastric acid
Mainie I, et al. Br J Surg. 2006;93:1483-1487. Image reproduced from Wikipedia Web site. http://en.wikipedia.org/wiki/Nissen_fundoplication. Accessed October 15, 2007.
We do not have data in pediatrics about fundoplication. Don Castell is going to show you his data. I am just borrowing it from him. This is a study in which fundoplication was done in adult symptomatic people that had a positive symptom correlation with impedance. They show that it was very good. I am going to let him present his data. We have a study at Childrens that we are completing with about 30 patients with fundoplication, so I hope that by the time DDW comes I can actually give you data on how does impedance work in children with fundoplication.
32
Efficacy of Baclofen in Reducing Incidence of TLESR and Acid Reflux*

Patients intubated with manometric/pH assembly and given 250 mL cows milk Esophageal motility and pH measured for 2 hours (control period) Baclofen or placebo administered Measurements performed for another 2 hours (test period)
* Randomized, double-blind, placebo-controlled trial; N = 30 (18 male, 12 female; mean age 10.0 0.8 years) P < 0.05 P < 0.01
Now regarding baclofen, as you know, there is 1 study uncontrolled in Japanese children in 9 kids with CP that it showed it was effective, but this is a landmark study from Dr. Omari in Australia.
33

Esophageal Motility and Acid GER Number of TLESRs % change Number of TLESRs + Acid GER % change Placebo Group Control Period 6.0 0.8 Test Period 5.3 0.6
- 6% [-38%, -18%] 1.9 0.4 1.9 0.4
0% [-38%, +63%]
(Data expressed as mean standard error of mean, or median [interquartile range])
* Randomized, double-blind, placebo-controlled trial; N = 30 (18 male, 12 female; mean age 10.0 0.8 years) P < 0.05 P < 0.01
What they did is they did a placebo-controlled study in which they gave baclofen and they measured baseline manometry. You can see the number of inappropriate relaxations, whether the relaxations gave you reflux or not,
34

Esophageal Motility and Acid GER Number of TLESRs % change Number of TLESRs + Acid GER % change Placebo Group Control Period 6.0 0.8 Test Period 5.3 0.6 Baclofen Group Control Period 7.3 1.5 Test Period 3.6 1.2
- 6% [-38%, -18%] 1.9 0.4 1.9 0.4
- 67% [-95%, -33%] 4.2 0.7 1.7 1.0
0% [-38%, +63%]
- 83% [-100%, - 75%]
(Data expressed as mean standard error of mean, or median [interquartile range]) * Randomized, double-blind, placebo-controlled trial; N = 30 (18 male, 12 female; mean age 10.0 0.8 years) P < 0.05 P < 0.01
and they compared placebo with baclofen. What you can see is baclofen significantly decreased the number of esophageal relaxations that were inappropriate and significantly decreased the number of reflux associated with these relaxations. Clearly, baclofen is something important. This is more a model of study, as you know. It has a lot of side effects, and that has been the biggest limitation.
35
Comparison of Reflux Profiles:

GERD Patients, Jejunal Feeding Patients, and Control Patients
60
Jejunal feeding patients

47.4
54.9 51.4
GERD patients Control patients

N = 13
Number of events
50 40 30 20 10 0
18.1
33.8 26.4 26.5 26.4
13.7 7.5 7.4 10.5
Acid events
(P = 0.003)
Nonacid events
(P = 0.02)
pH-only events
(P = 0.04)
Total MII events

(P = 0.07)
There were no differences between the heights and the total numbers of reflux events between GERD and jejunal feeding patients
Rosen R, et al. J Pediatr Gastroenterol Nutr. 2007;45(suppl 7):E40-E41. Abstract 105.
Finally, we will use J-tube feeds. I think our experience is that J-tube feedings really work in some of these children. We tried to see what was the effect of J-tube feedings on reflux, and to our surprise, this is the data we are presenting here. We found that children on J-tube feeds that were not being fed gastrically had the same amount of reflux as compared to patients with GERD or controls. It is interesting. I do not know exactly how J-tubes work. They do work. Maybe it is the amount of refluxate. Impedance dosing lets you see if the volume is decreasing. J-tube feeds do not change the amount of reflux you have. So, these patients continue to need to be treated.
36
Summary
GERD is common and has a significant impact GERD in children is a chronic condition Acid is the main insult Nonacid reflux may play a role in intractable patients, and those with atypical symptoms New therapies are needed
Thank you.
37

Continue
The Role of Nonacid and Acid Reflux in GERD

The Adult Perspective
Professor of Medicine Director of Esophageal Disorders Program Digestive Disease Center Medical University of South Carolina Charleston, SC
Donald Castell, MD
(Dr. Gold) So, we are moving on into the adult perspective. I am really honored to be in the presence of and to listen to what you are about to hear. Dr. Don Castell, professor of medicine and director of the Esophageal Disorders Program and Digestive Diseases Center in Charleston, South Carolina, at MUSC is going to talk about the role of nonacid and acid reflux in GERD from the adult perspective. Dr. Castell. (Dr. Castell) Thank you Ben. Good evening everybody. It is truly a pleasure to be here with you. There is a great limitation in what I know about pediatric reflux, but we are going to talk about what I know about adult reflux. I have been doing this disease for 40 years, if you will. People call me an esophagologist. The definition is an individual who makes a living out of heartburn, whereas most people get heartburn from making a living. We are going to talk about what we esophagologists have done.
Pathophysiology of Gastroesophageal Reflux

The role of acid is well established Symptoms persist in many patients despite adequate acid suppression
PPI therapy does not change the pathogenesis of reflux PPI therapy does not stop postprandial reflux; it only changes the pH of the refluxate
Could nonacid reflux be the culprit?

Reflux mechanisms not changed How to make the diagnosis? What is its prevalence? Is it clinically important? How to treat?
We have heard some really nice reviews on the pathophysiology of reflux disease. This is by and large an acid disease. The role of acid is well established, but every one of you see patients today that are still having symptoms despite adequate acid suppression. The questions that have evolved then recognize the fact that when you put somebody on a PPI it does not change the pathogenesis of reflux, that is the abnormal motility, the permissive lower esophageal sphincter. PPI therapy, therefore, does not stop postprandial reflux; it only changes the pH of the refluxate. So, the question that has arisen over the last decade is could these symptoms be related to nonacid reflux? The short answer is, Of course, why not? We are going to address the fact that, yes, the reflux mechanisms are not changed. How do we make the diagnosis? What is its prevalence? Is it clinically important? Bottom line, we will talk a little bit about how we would probably treat these patients.
Meta-analysis of PPIs Versus H2RAs for Erosive Esophagitis Healing

Healing rate ratio (95% CI) vs. ranitidine 300 mg
Lansoprazole 30 mg (n = 948) Omeprazole 20 mg (n = 1575) Pantoprazole 40 mg (n = 249) Rabeprazole 20 mg (n = 338) 0.75 Favors H2RA 1.0 1.25 1.5 1.75 2.0
Favors PPI
PPIs were superior to ranitidine for healing of esophagitis at 8 weeks

P < 0.05 for all PPIs vs. ranitidine 300 mg
Caro JJ, et al. Clin Ther. 2001;23:998-1017.
Now, come back to the acid for just a minute. This is a very nice meta-analysis that you see summarized in front of you. It basically compared healing rates of erosive esophagitis with the 4 proton pump inhibitors shown in the left versus ranitidine the H2 receptor antagonist. Again, no surprise to anybody in the room, showing that the greater the suppression of acid the better the healing rate of esophagitis. PPIs won hands down over the H2 blocker.
Percentage Healing by Baseline Erosive Esophagitis Grade

Lansoprazole 30 mg
Percentage of patients healed
Esomeprazole 40 mg
P < 0.01 (Cochran-Mantel-Haenszel test)
100 80 60 40 20 0
91.3
91.7 86.0 86.3 74.6 62.1 84.6 79.7
Grade A (n = 1878)
Grade B (n = 2076)
Grade C (n = 959)
Grade D (n = 327)
Castell D. Am J Gastroenterol. 2002;97:575-583.
I was fortunate to the be the first author of this, what is the largest multicenter study ever done in the treatment of reflux disease with PPIs, over 5000 patients from the United States, and we separated them into grades A, B, C, and D, the Los Angeles classification for reflux disease. What you see is that again healing rates vary from an average of about 80% to over 90% depending on the severity of the esophagitis. So, there is no question that we can heal this erosive disease.
Persistent Symptoms Are Common on PPI Therapy

Symptom response to PPI therapy among patients with nonerosive reflux disease (NERD) and erosive esophagitis (EE)
60
Percent of patients with symptom response
55.5
50 40 30 20 10 0
n = 1854 9.5 7.5
36.7
(P < 0.0001) (P > 0.05)
PPI response Placebo response
NERD
n = 705
Dean BB, et al. Clin Gastroenterol Hepatol. 2004;2:656-664.
EE
The problem is shown here. What about symptom resolution? This again is a review paper by Dean and Ronnie Fass group out at the University of Arizona. Basically, if you look at the right-hand side of the slide, these are the results in a group of patients with erosive esophagitis comparing the responsive symptoms to a PPI in yellow versus a placebo in white, but notice there is an excellent symptom response, but it is only 55% of the patients that are without any residual symptoms. Over in the nonerosive reflux group, what we call NERDsdo you guys do that, do you call them NERDs?the results are even much worse. Only about a third of these patient became totally asymptomatic with their PPI therapy. So, do symptoms continue despite acid suppression? Absolutely. I think we have begun to recognize that over the last few years.
Audience Question
Which diagnostic test can detect nonacid reflux (reflux with pH 4)?
1. 2. 3. 4. Barium esophagram pH-metry Combined impedance-pH (MII-pH) monitoring Endoscopy
All right, it is time for you to step up to the plate here. Audience questionwhich diagnostic test can detect nonacid reflux? And Im going to define that as reflux with a pH of 4 or greater. I want you to vote: 1. Barium esophagram 2. pH-metry 3. Combined impedance pH (MII-pH) monitoring 4. Endoscopy

Which diagnostic test can detect nonacid reflux (reflux with pH 4)?
Barium esophagram
3%
pH-metry
4%
Combined impedancepH (MII-pH) monitoring Endoscopy
91%
2%
Well, obviously the message is coming across loud and clear. If you really want to measure nonacid reflux, you have to have the right tool to do it with. So, lets talk a little bit more about this tool. Again, this is a little bit of a mini-summary here. You have heard all of this already.
Ambulatory MII-pH Monitoring

Detects gastroesophageal reflux of all types at multiple levels of the esophagus With this technique, MII detects the presence of the reflux, whereas the pH only indicates whether it is acid or nonacid
Acid reflux = pH < 4 Nonacid reflux = pH 4 Weakly acidic reflux = pH 4 7 Usually not bile
MII = multichannel intraluminal impedance
Zerbib F, et al. Am J Gastroenterol. 2006;101:1956-1963. Sifrim D, et al. Gut. 2004;53:1024-1031.
Ambulatory combined impedance and pH; the combined technology is the key. It detects reflux of all types at multiple levels in the esophagus. With this technique, the impedance detects the presence of a liquid reflux or of a gas reflux, whereas a pH only indicates whether it is acid or nonacid. So, your pH electrode now becomes a qualitative marker that identifies what type of reflux impedance is showing you. For 30 years we have used a pH of less than 4 as our threshold for acid reflux. That is why I prefer the term nonacid reflux to cover any refluxate with a pH above 4. However, strictly speaking chemically, weakly acidic applies correctly to the refluxate with a pH between 4 and 7. Please understand, if you simultaneously measure bile with a bilirubin detector in the esophagus that most of the nonacid reflux does not contain bile. Most of it is the food that the patient has ingested.
Combined MII-pH Catheter
pH catheter
LES
Adapted from Mainie I, et al. Br J Surg. 2006;93:1483-1487.
Let me show you the catheter we have been using. Up until 5 years ago, if I was referred a patient who was symptomatic on a PPI, this is what I would have done; in fact, what we did.
pH catheter
5 cm
Esophageal pH
LES
Gastric pH
We placed a pH catheter with dual electrodes, 1 down here in the stomach so that I could monitor how well we had controlled gastric acid and a second one up here 5 cm above the LES, so I could measure whether there was ongoing reflux, acid reflux if you will.
10
pH catheter
5 cm
Esophageal pH
LES
Gastric pH
Now, we would modify that catheter here by placing a series of rings, as you saw earlier, so that impedance is measured between each pair, the electrical resistance is sampled.
11
pH catheter
Impedance
17 cm 15 cm
9 cm 7 cm 5 cm 3 cm
5 cm
Esophageal pH
LES
Gastric pH
This allows me now to measure the presence of fluid at 3, 5, 7, 9, 15, and 17 cm above the lower sphincter.
12
MII- pH catheter
Impedance
17 cm 15 cm
9 cm 7 cm 5 cm 3 cm
5 cm
Esophageal pH
LES
Gastric pH
That is the MII-pH catheter. The data that I am going to show you subsequently were all collected using that catheter.
13
Postprandial Reflux Becomes Predominantly Nonacid During Treatment With Omeprazole*

Total number of reflux episodes
300
n = 261
n = 254
250 200 150
n = 217 (97%) n = 119 n = 98
100 50 0 No Rx
Total (P = ns) Acid (P = 0.02)
(45%)
(55%)
n=7 (3%)
On PPI
Nonacid (P = 0.03)
PPI therapy does not stop postprandial reflux it only changes the nature of the refluxate
*2-hour postprandial
Vela MF, et al. Gastroenterology. 2001;120:1599-1606.
This was the original seminal study that we did at the graduate hospital in Philadelphia. You will notice down at the bottom the first author, a young man by the name of Marcella Vela from Guatemala. If you do not know Marcella, I hope you get to know him. He is very bright. His partner in crime here was a man from Romania by the name of Radu Tutuian, also a very bright young investigator. We worked with these 2 young men, Phil Katz and myself. This was the study. We basically asked the question, If I take a group of patients with regular GERD symptoms, people with heartburn 3 times per week or more, and I take them off their therapy, give them a big meal that induces reflux and test them with this new device, what do I find? That is what is shown on the left. So, 12 individuals, 2 hours postprandial. This is only a postprandial study right now. There were 217 reflux episodes. Most of them, here in the gray, 55% were nonacid because the meal has buffered the gastric contents for the first hour particularly, then it becomes more acidified for the second hour. Your pH probe does not tell you this is happening. Then we put the patients back on their PPI for a week, and we redid the experiment. What happened? Well, we did not change the number of reflux episodes, but we got rid of the acid. So, now 97% of them are nonacid. As the slide says at the bottom, PPI therapy does not stop postprandial reflux, it only changes the nature of the refluxate. You would not expect if would do otherwise.
14
PPI Therapy Does Not Decrease Postprandial Reflux

On PPI (n = 70)
5.7
Off PPI (n = 40)

5.8 4.4
6 5
Nonacid Acid
6 5 4 3
Episodes per hour
4 3 2 1 0 Total
3.3
2.3
1.7
2 1 0
1st hour 2nd hour postprandial postprandial
Total
1st hour postprandial
2nd hour postprandial
Blonski W, et al. Gastroenterology. 2007;132(4 suppl 2):A-288. Abstract S1959.
Now, we have looked at the same thing just recently in 24-hour monitoring. This is a slide by Wojciech Blonski, a young investigator from Poland who was working with us in the laboratory. These are his data presented at DDW earlier this year. On the left, the results in 70 patients studied for 24 hours with impedance pH on PPI therapy. Average number of reflux episodes per hour in the total study was 1.7, about 2 per hour, but after a meal, the first hour, almost 6 per hour and a little less in the second hour. A group of 40 patients studied off PPI, the results numerically are exactly the same, a little bit more basal reflux, about 2.3 episodes per hour, the same amount of postprandial reflux, the second hour a little bit more. The differences are, as you would expect, the acidity. Over here on PPI therapy, most of the reflux episodes, the gray parts of the bar, are nonacid. Over here off PPI, most of the reflux, the yellow portions of the bar, are acid. So, again, it confirms very nicely what you would expect.
15
MII-pH in Patients With Symptoms on PPI BID

Patients Patients experiencing experiencing persistent persistent symptoms symptoms despite despite PPI PPI therapy therapy n n= = 200 200
SI = symptom index
Mainie I, et al. Br J Surg. 2006;93:1483-1487.
Now let me show you what we have learned in studying your group of patients that were referred to me because they were symptomatic despite PPI therapy. In fact, I often like to stop at this point with a group of gastroenterologists and ask the question, When is the last time you saw a patient with GERD that was not already taking a PPI? In the adult world, the answer is almost always Never. We do not see PPI-naive patients anymore. So, here I am showing you the results of the first 200 patients that we studied with this technology that have persistent symptoms despite PPI therapy at least BID. That is the buy-in. They have to be taking a standard PPI before breakfast and before dinner. We now have data, by the way, in another 200, so we have over 400 patients studied. Now, we did a pretty good job. You know, when you put a catheter down somebodys nose, and somebody has already alluded to this, in order to get cooperation, you have to tell them what is happening here and what the importance of the study is and that they should go out and if they know what brings on their symptom they should do it that day.
16

Patients Patients experiencing experiencing persistent persistent symptoms symptoms despite despite PPI PPI therapy therapy n n= = 200 200
No No symptoms symptoms during during 24-hour 24-hour MII-pH MII-pH monitoring monitoring n n= = 28 28 (14%) (14%)
SI = symptom index
Only 14% of our patients failed to have symptoms during their 24-hour monitoring;
17

Patients Patients experiencing experiencing persistent persistent symptoms symptoms despite despite PPI PPI therapy therapy n n= = 200 200 Symptoms Symptoms during during 24-hour 24-hour MII-pH MII-pH monitoring monitoring n n= = 172 172 (86%) (86%)
SI = symptom index
86%, therefore, were symptomatic.
18

+ SI
Nonacid Nonacid reflux reflux n n= = 61 61 (35%) (35%)

SI = symptom index Mainie I, et al. Br J Surg. 2006;93:1483-1487.
What did we find in those 172 patients? Well, positive symptom index for reflux with their symptom with nonacid reflux about 35%.
19

+ SI
+ SI

SI = symptom index
Acid Acid reflux reflux n n= = 13 13 (8%) (8%)
The least common finding is a positive symptom index for ongoing acid reflux. In our experience, you can almost take that to the bank. If you have somebody on a PPI twice per day appropriately dosed, they should not be having acid as a cause of their continuing symptoms.
20

SI
Symptoms Symptoms not not associated associated with with reflux reflux n n= = 98 98 (57%) (57%)
+ SI
+ SI

SI = symptom index
Acid Acid reflux reflux n n= = 13 13 (8%) (8%)
It is not 100%, but pretty close. As you have already figured out, the most common finding was that the symptoms were not associated with reflux, 57%. When we first did this, we said, Darn, that is kind of a negative result, but do not underestimate the clinical utility of that finding; that allows you to essentially eliminate reflux as a cause of the ongoing symptoms and to direct your approaches in another direction.
21
Symptom Reflux Association in Patients On and Off PPI Therapy

Off PPI therapy:
Acid GER: Nonacid GER:
74 patients
51% +SAP 24% +SAP
On PPI therapy:
Acid GER: Nonacid GER:
60 patients
20% +SAP 32% +SAP
Regurgitation and cough had most frequent association with nonacid GER
SAP = symptom association probability
Zerbib F, et al. Am J Gastroenterol. 2006;101:1956-1963.
Now, similar results have been published at actually the same time as ours. The 2 papers both came out last year by Frank Zerbib and colleagues from France. It is a French-Belgium consortium multicenter study. They studied again 74 patients off PPI and showed that the symptom association probability was more likely to be acid reflux in that group than nonacid, but like our 200 patients, here are 60 patients on PPI, they found 20% ongoing acid reflux, but almost the same frequency of nonacid reflux with symptom probability, 32%. They commented that regurgitation and cough had the most frequent symptom association with nonacid reflux.
22
Audience Question
Which of the following medications decreases transient lower esophageal sphincter relaxations?
1. 2. 3. 4. Metoclopramide Lansoprazole Imipramine Baclofen
All right, question again: which of the following medications decreases transient lower esophageal sphincter relaxations? 1. Metoclopramide 2. Lansoprazole 3. Imipramine 4. Baclofen
23

Which of the following medications decreases transient lower esophageal sphincter relaxations?
Metoclopramide 6%
Lansoprazole
4%
Imipramine
5%
Baclofen
85%
All right, again, everybody has the right message here. Although lansoprazole as a PPI would be very effective in healing esophagitis and treating many, many patients, it does not affect these transient relaxations. Although imipramine, as we will talk about in a minute, may be effective in changing the visceral sensation the patient is feeling, it does not affect transient relaxations. Metoclopramide does not also affect them. Baclofen would be the drug.
Symptomatic Nonacid Reflux: Reflux Reduction Therapy

Medical To decrease transient lower esophageal sphincter relaxations (TLESRs): baclofen To increase lower esophageal sphincter pressure (LESP): bethanechol To improve gastric emptying: metoclopramide, domperidone To decrease visceral sensation: imipramine To decrease reflux: alginic acid PRN Endoscopic Surgical Fundoplication
Agrawal A, et al. Practical Gastroenterol. 2006;30:68-72. Peghini PL, et al. Gut. 1998;42:807-813.
Symptomatic nonacid reflux: I want you to begin to think about reflux reduction therapies rather than acid reduction therapies, which is what you do when you give a PPI. Medically, we talked about baclofen because it will decrease transient LES relaxations. What about raising the resting LES pressure? Reach back now for an older drug, bethanechol, that actually can be effective in some of these patients. What about trying to improve gastric emptying if the patients have delayed gastric emptying? Here again a more standard promotility drugagain, wouldnt it be nice if we had oneshould be considered. I mentioned imipramine already as a way to decrease the patients sensation from the reflux episodes because you could take the approach that with the acid removed the damaging aspect is no longer there. If I can get rid of the symptoms with a drug like imipramine, then I should consider that. We use Gaviscon with its alginic acid component as a PRN therapy for these. There is minimal evidence from controlled studies on any of these. I will show you one study with baclofen in just a minute. Is there an endoscopic approach? Again, I wish there was. We keep looking because I believe that of all the patients we see, the patient who is still symptomatic despite good acid control is a candidate for a reflux reduction procedure. Surgery, that is a fundoplication, as has already been mentioned, obviously immediately comes to the fore.
25
Effect of Baclofen on Acid and Nonacid Reflux

300
253
Placebo Baclofen
Number of reflux episodes
250 200 150 100 50

15* 151
77* 59*
72 30 3*
0 Total
*P < 0.05
Vela MF, et al. Aliment Pharmacol Ther. 2003;17:243-251.
Acid
Nonacid
Re-reflux
Now, a couple of quick slides on baclofen. Again, Marcella Vela, before we left Philadelphia at the beginning of this decade, did a study with baclofen compared to placebo in a group of patients with reflux and showed that if you look at the number of reflux episodes, baclofen (shown in yellow) significantly decreased total reflux, acid reflux, nonacid reflux, and acid re-reflux because of the transient LES relaxation effect.
26
Baclofen Decreases Acid GER and Symptoms

28 patients and 15 controls Both 24-hour study and 4-week trial with baclofen 10 mg QID vs. placebo
Baclofen decreased GER episodes and percentage of time pH < 4 (acute and chronic) Baclofen decreased acid GER and symptoms
Side effects: dizziness, anxiety
Ciccaglione AF, et al. Gut. 2003;52:464-470.
The one controlled study, it is a small one that is in the literature, came from Italy with 28 patients and 15 controls. They did both a 24-hour pharmacologic study, if you will, and a 4-week trial with baclofen 10 mg 4 times per day versus placebo. It showed that baclofen decreased episodes of reflux and the percent time that the pH was less than 4. They were looking at pH here by the way, both in the acute and chronic study. Baclofen decreased acid reflux and symptoms, and the side effects were CNS in typedizziness, anxietyand the things that you know about with this drug.
27
In your experience, under what conditions should surgery be recommended for patients?
All right. This is an interaction question. In your experience, under what conditions should surgery be recommended for GERD patients? That is a fundoplication, if you will. (Dr. Furuta) We have a volunteer back here, Don. (Audience) What about reflux nonresponsive to medical therapy? (Dr. Castell) OK. (Audience) Pathologic reflux. (Dr. Castell) Pathologic reflux that has not responded to therapies. (Dr. Gold) Don, we have a volunteer right here, too. (Dr. Castell) Where are you? I cannot see you. (Dr. Gold) I am all the way in the back. (Dr. Castell) OK. Yes. (Audience) This is Dr. Chandra from Pittsburgh. The response to surgery is poor and unpredictable, so under very, very careful circumstances you have to tell them that the control is not permanent. It comes back in a lot of people and varying time. So, this is not a correction of the pathophysiological process, it is a placebo procedure. It does not correct the pathophysiology, it induces a vagal damage in many patients and increases the gastric emptying problems, so surgery has not been very successful in our group of patients that I have followed over the last 30 years. (Dr. Castell) All right. One more comment. (Dr. Gold) We have one in the back. (Audience) I am from Chicago. I think I would support and not support surgery with fundoplication. I can give an example, there was a child I looked after without neurological deficit, had a 3-4 cm hiatal hernia, had grade C LA classification of esophagitis, responded to 90 mg of lansoprazole. Because the child responded, then I sent the child to surgery, and the child had a very good outcome because the child had a great pediatric surgeon. Also, in children with neurological deficits and chronic respiratory problems, we all as a group who are sitting here know the outcome is not very good. (Dr. Castell) Thank you very much for your comments everybody. I think we heard some of the things that we all understand about surgery. It does have its limitations. It does have the tendency for extra effects. Some relapses certainly do occur, but also with the right surgeon and the right selection of patients, I think, can be a very good procedure.
28
A Surgical Approach to Patients Who Fail Acid Suppression Treatment

19 patients undergoing LNF (10 atypical symptoms; 9 typical symptoms)
LNF = laparoscopic Nissen fundoplication
Let me show you the piece of outcomes data that we obtained at the Medical University of South Carolina. Again, these are from those first 200 patients that we monitored that were on a PPI twice per day. Nineteen patients that had a laparoscopic Nissen fundoplication, interestingly, half of them, 10 that is, had atypical GERD symptoms, that is supraesophageal symptoms; the other 9 had typical GERD symptoms. Here were the diagnostic findings.
29

19 patients undergoing LNF (10 atypical symptoms; 9 typical symptoms) Patients with positive symptom index (nonacid) (n = 14)
Positive symptom index for nonacid reflux was 14 patients. Interestingly, half of them had chronic cough. I will show you the response in a minute.
30

19 patients undergoing LNF (10 atypical symptoms; 9 typical symptoms) Patients with positive symptom index (nonacid) (n = 14) Patients with positive symptom index (acid) (n = 4)
Four patients had a positive symptom index for acid.
31

19 patients undergoing LNF (10 atypical symptoms; 9 typical symptoms) Patients with positive symptom index (nonacid) (n = 14) Patients with positive symptom index (acid) (n = 4) Patients with symptoms not associated with reflux (n = 1)
One patient, by the way, did not have reflux demonstrated with symptoms, but the surgeon operated anyway; that was a failure and is one of our controls, if you will.
32

94% of patients with positive symptom index were asymptomatic or markedly improved after mean follow-up of 14 months (range 7-25 months)
Here are the results in the 18 patients that actually had reflux demonstrated by testing, 17, that is 94%, were still off PPI with symptom response at the end of the 14 months follow-up, which was the period of time that we followed them.
33

94% of patients with positive symptom index were asymptomatic or markedly improved after mean follow-up of 14 months (range 7-25 months)
Patients with a positive symptom index resistant to PPIs with nonacid or acid reflux demonstrated by MII-pH monitoring can be treated successfully by laparoscopic Nissen fundoplication
LNF = laparoscopic Nissen fundoplication Mainie I, et al. Br J Surg. 2006;93:1483-1487.
So, we concluded that patients with a positive symptom index that are resistant to PPIs with nonacid or acid reflux demonstrated by impedance pH monitoring can be treated successfully with a Nissen fundoplication.
34
Changing GERD Paradigm

Pre-PPI (United States 1989)
Esophageal acid exposure (DeMeester score) Mucosal injury (erosive esophagitis/stricture) Symptom relief secondary end point
PPI honeymoon (1989-2004)

Acid exposure/score less important Continued symptoms on treatment Gastric acid control incomplete (nocturnal breakthrough) More aggressive acid control Continued symptoms
I want to end up by sharing with you my changing view about reflux as somebody who has watched it over many years. Prior to 1989, that is the pre-PPI era, the world changed with omeprazole; esophageal acid exposure and things like the DeMeester score were important because we did not have a good way to control the acid. Mucosal injury was rampant. Esophagitis and strictures, which we see much less of today, were present. Symptom relief was a secondary end point.
35


What I like to call the PPI honeymoon, from about 1989 with omeprazole and others until about 2004; acid exposure and the score now are less important because we can control the acid pretty well, but we see continued symptoms in some of these patients. We learned that gastric acid control was not as complete as we thought it might be and things like nocturnal breakthrough are described, so we used more aggressive acid control. Yet, there is a group of patients with continued symptoms.
36


37

Total reflux awareness (after 2004)
Impedance technique identifies nonacid reflux Symptom association has greater importance since PPIs have healed esophagitis Reflux reduction treatments must be considered
This brings me to what I like to call the total reflux awareness era after 2004, where the impedance technique allows us to measure all of the reflux and understand the disease and the symptoms better. Symptom association has greater importance than does the amount or the frequency of reflux since PPIs have healed the esophagitis. We need to find better reflux reduction treatments.
38
Summary
A positive symptom index for nonacid or acid reflux using MII-pH predicts successful response to laparoscopic Nissen fundoplication Surgery is OK for PPI failures if reflux as a cause of symptoms has been shown by MIIpH testing Other reflux reduction therapies are needed
Thank you very much for listening.
39

Continue
What Do Eosinophils in the Esophagus Really Mean:

Acid, Allergy, or Something Else?
Glenn T. Furuta, MD
Associate Professor University of Colorado at Denver and Health Sciences Center Denver, CO
(Dr. Gold) All right and now moving on to the last, but definitely not least, and I think something that all of you have been excited about at some point. We had the opportunity last year preceding the NASPGHAN meeting to hear a whole day. We are going to have Glenn Furuta, who still says that he is a Red Sox fan, although now lives in Denver. He is the associate professor at the University of Colorado and Health Sciences Center. He is going to discuss: What Do Eosinophils in the Esophagus Really Mean, Acid, Allergy or Something Else? (Dr. Furuta) Thank you Ben. Ben and I have known each other for a long time, and one of the early lessons that he taught me was always have a SOCO (Single Overriding Communicable Observation). So, it is late, and I know you guys have been sitting in meetings all day; and if you took nothing else away from my presentation, I think in 2007 the real message is that eosinophilic inflammation is a multifaceted histological finding that has a diverse set of etiologies. We have started to understand more about eosinophilic disease. We have identified it as a finding in reflux disease, but the upcoming decades are really going to lend us to more investigations of understanding it is a hallmark of other disease; and it is the challenge for all of the fellows and the trainees in the room.
Audience Question
A patient presents with dysphagia, food impaction, and reflux-like symptoms. The patients pH monitoring records normal pH levels. The patients endoscopy reveals whitish plaques and longitudinal shearing. Based on this information, what is the diagnosis for this patient? 1. GERD 2. Eosinophilic esophagitis 3. Not enough information
So, we are going to start with an audience questions about eosinophilic esophagitis and eosinophilic inflammation. A patient presents with dysphagia, food impaction and reflux-like symptoms. The patients pH monitoring records normal pH levels. The patients endoscopy reveals whitish plaques and longitudinal shearing. Based on this information, what is the diagnosis? 1. GERD 2. Eosinophilic esophagitis 3. Not enough information

A patient presents with dysphagia, food impaction, and reflux-like symptoms. The patients pH monitoring records normal pH levels. The patients endoscopy reveals whitish plaques and longitudinal shearing. Based on this information, what is the diagnosis for this patient?
GERD Eosinophilic esophagitis Not enough information
1%
70%
29%
OK. So, it is an interesting question, and I think an interesting set of answers. We put this question in to emphasize the fact that the diagnosis of eosinophilic esophagitis needs to be made with a biopsy. So, if you are limited in your findings and not able to have a pathologist available, then certainly eosinophilic esophagitis would be the first diagnosis. I think the thing that would cue you in is the longitudinal shearing, but you need to have a biopsy, so the real answer is #3, get a biopsy.
Differentiating GERD From Eosinophilic Esophagitis

GERD
Pathogenesis Transient relaxation of lower esophageal sphincter Heartburn, epigastric pain, Symptoms vomiting/regurgitation Exudate, friability, erosions, Endoscopy ulceration
Eosinophilic Esophagitis*
Possibly allergic Dysphagia, food impaction, reflux-like symptoms Longitudinal shearing, furrows, rings, whitish plaques
Histology Eosinophils, basal zone hyperplasia, papillae elongation pH monitoring Acid reflux Treatment PPI Long-term Strictures (distal), cancer complications Normal Steroids, dietary elimination Strictures (proximal)
*No pathognomonic findings
Arora AS, et al. Clin Gastroenterol Hepatol. 2004;2:523-530.
So, how do we differentiate eosinophilic esophagitis from reflux disease. I think you have probably and hopefully will see the consensus statement that came out in Gastroenterology this month that was a compilation of 32 physicians from a number of different subspecialties including pathology, allergy, and gastroenterology, both adult and pediatric, that helped us to try to differentiate some of the features of this disease, but more importantly identify diagnostic criteria. I think the bottom line is that in the bottom left-hand corner of this slide is that there are no pathognomonic findings yet for eosinophilic esophagitis. In fact, the pathogenesis of this disease, as you have heard for reflux, suggests that it is a function of transient relaxations of the LES. Eosinophilic esophagitis, indeed, may have an allergic etiology. The symptoms can cross over, and there are no real symptoms that truly identify or separate these diseases, but they are shown here. Endoscopically, longitudinal shearing is probably one of the few features that is fairly specific, but because the finding is somewhat unusual, there have not been studies yet to identify it as the only finding that would separate the 2 diseases. The histology can appear the same in both disease. In data that we have presented last year, we will show a little bit later in the presentation, clearly you can have increased numbers of eosinophils in both reflux, as well as EE. pH monitoring is suggestive if there is a normal pH probe in EE. The treatments obviously are quite different and well known to you. We think that one of the other separating features might be the fact that there are proximal strictures in EE and not in GERD, but again there is not enough data yet to truly make that statement.
Differentiating GERD From Eosinophilic Esophagitis

GERD
Pathogenesis Transient relaxation of lower esophageal sphincter Heartburn, epigastric pain, Symptoms vomiting/regurgitation Exudate, friability, erosions, Endoscopy ulceration
Eosinophilic Esophagitis*
Possibly allergic Dysphagia, food impaction, reflux-like symptoms Longitudinal shearing, furrows, rings, whitish plaques
Histology Eosinophils, basal zone hyperplasia, papillae elongation pH monitoring Acid reflux Treatment PPI Long-term Strictures (distal), cancer complications Normal Steroids, dietary elimination Strictures (proximal)
Exclude GERD before making diagnosis of eosinophilic esophagitis

*No pathognomonic findings Arora AS, et al. Clin Gastroenterol Hepatol. 2004;2:523-530.
I think before making the diagnosis of eosinophilic esophagitis, one needs to exclude GERD first.
Audience Question
Endoscopic findings that are pathognomonic for eosinophilic esophagitis include which of the following?
1. 2. 3. 4. 5. Longitudinal furrows White nodule- or plaque-like exudates Transient or fixed corrugated rings 2 and 3 None of the above
The second questionendoscopic findings that are pathognomonic for eosinophilic esophagitis include which of the following? 1. Longitudinal furrows 2. White nodule or plaque-like exudates 3. Transient or fixed corrugated rings 4. 2 and 3 5. None of the above

Endoscopic findings that are pathognomonic for eosinophilic esophagitis include which of the following?
Longitudinal furrows White nodule- or plaque-like exudates Transient or fixed corrugated rings 2 and 3 None of the above
16% 2% 5% 30% 47%
OK, well, certainly I think I have tried to emphasize before the fact that all of the features that can be seen endoscopically in eosinophilic esophagitis likely represent inflammation; and whether that is swelling of the squamous epithelium, exudation of eosinophils through the epithelium, or fixed or transient motility disturbances, all of these are relatively nonspecific. There have not been any studies yet to truly identify any of these as pathognomonic for eosinophilic esophagitis.
Eosinophilic Esophagitis Compared to Erosive Esophagitis

Eosinophilic esophagitis1
Erosive esophagitis2
1Reproduced
with permission from Hawari R, et al. N Engl J Med. 2007;356:e20. Copyright 2007. Massachusetts Medical Society. All rights reserved. 2Image courtesy of G. Triadafilopoulos, MD.
So, we wanted to talk a little bit about the eosinophils themselves and their life cycle and how eosinophils may, in fact, contribute to esophageal dysfunction.
Eosinophil Life Cycle

Eosinophils primarily reside in organs with mucosal surfaces Eosinophils are born from bone marrow progenitor stem cells and mature to a fully granulated state before migration to vascular spaces
Furuta GT, et al. Aliment Pharmacol Ther. 2006;24:173-182.
In that light, eosinophils primarily reside in organs with a mucosal surface; so, any organ that resides exposed to the environment has eosinophils present, so the eyes, the gut, and the genitourinary tract. They are born from the bone marrow progenitor cells and mature into a fully granulated state before they migrate into the vascular spaces.
Eosinophil Life Cycle (cont.)

Interleukin (IL)-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) control maturation
IL-5 is the most specific for eosinophils IL-5 also stimulates release of eosinophils from the bone marrow and extends their survival once in target tissues
Furuta GT, et al. Aliment Pharmacol Ther. 2006;24:173-182.
Importantly, one of the cytokines that is critical in the development of eosinophils is interleukin-5; interleukin-3 and GM-CSF also participate in that maturation, but, in fact, IL-5 is the most specific for eosinophils.
10
Eosinophil Life Cycle (cont.)
Maturation
GATA-1 PU.1 c/EBP IL-3 GM-CSF IL-5 IL-5 m2 L2 ICAM-1
Bone Marrow
Migration
Blood
41 4 7 VCAM-1 MadCAM-1
Eotaxin-1
GI Tract
Adapted from Rothenberg ME, et al. Annu Rev Immunol. 2006;24:147-174.
In addition, IL-5 can stimulate the release of eosinophils from the bone marrow into the vascular space and then help in their survival once they arrive in a mucosal surface. That is shown here in this diagram. One can see the bone marrow, the vascular space, and then the target organ tissue. They are born here under the direction of specific transcription factors. You can see the cytokines that are involved in their maturation. Under certain beckoning calls, they migrate to the vascular space, where they reside briefly. Then, under the direction of specific adhesion molecules that we will discuss in a few minutes, migrate through the endothelial space and into the mucosal surfaces. In those mucosal surfaces, they encounter other cytokines and other activating factors that may allow them to participate in both host health and disease.
11
Is esophageal eosinophilia induced by exposure to acid, or exposure to allergens?
So our audience interaction question: Is esophageal eosinophilia induced by exposure to acid or exposure to allergens? (Dr. Gold) Volunteers? We have an answer for your question, Dr. Furuta. (Audience) The answer is Yes. (Dr. Furuta) Acid disease. (Audience) That is great. (Dr. Gold) There is a fence-sitter for you. (Audience) It depends upon what the lab tech says the baseline is for eosinophilic esophagitis, if the number is 10 per high-power field or 20 or more than 20. So, the whole diagnosis is dependent on the individual lab as for eosinophilic esophagitis. (Dr. Furuta) So, you are saying the number of eosinophils dictates which. So, I am glad you brought it up. I think it is an important discussion to have. We will show some evidence that may support that in one sense, but I think what we have learned now and if we looked at the history of eosinophilic inflammation of the esophagus, the original description was by Harland Winter, who noted that there were greater than 1 eosinophils present in the esophagus of children affected with reflux disease. It was only characterized in that sense of greater than 1. We have learned over time that there are better ways to quantify that in the sense that there are likely higher numbers that are associated with reflux disease. Now that we have seen another clinical phenotype of patients who have symptoms that are nonresponsive to acid blockade, they have larger numbers, also. We will address this in just a few minutes. Any other answers?
12
Acid-Inducing Eosinophilic Esophageal Inflammation
So, we wanted to touch on this evidence that may suggest that, indeed, eosinophils can arrive in the esophagus, and what is some of the basic evidence to support that observation.
13
GERD and Esophageal Eosinophilia

GERD causes esophageal injury, resulting in infiltration of eosinophils
Acid induces:
Epithelial cells to express adhesion molecules recognized by ligands on the eosinophil Esophageal epithelium to release chemokines that attract eosinophils
Spechler SJ, et al. Am J Gastroenterol. 2007;102:1301-1306.
So, GERD can cause esophageal injury. We have certainly heard a lot about that this evening. It can result in infiltration of eosinophils. As I said, Harland (Winter) had identified this very early on, but only classified it in the sense of greater than 1. Acid can induce epithelial cells to express adhesion molecules that, indeed, can cause them to transmigrate and attach to the endothelial surface. Esophageal epithelial cells can release chemokines that may attract eosinophils.
14
GERD and Esophageal Eosinophilia (cont.)

GERD causes esophageal injury, resulting in infiltration of eosinophils
Acid increases:
Esophageal blood flow, enhancing delivery of eosinophils
GERD and eosinophilic esophagitis coexist, but are unrelated
Now, both of these points and the following point have been brought up on very provocative articles that were written by Stuart Spechler in the last 6 months suggesting that there may be mechanisms for this to happen; but, in fact, there has been very little in the sense of basic evidence to support these findings yet. Additionally, esophageal blood flow can be increased by acid injury that could enhance the delivery of eosinophils, again, in observation, but not anything that has been yet supported by basic or translational evidence. So, GERD and eosinophilic inflammation may coexist, but may be unrelated.
15
GERD and Esophageal Eosinophilia (cont.)

Eosinophilic esophagitis may contribute to GERD
Eosinophil products possibly alter esophageal motility to:
Induce reflux Slow clearance of refluxate
Eosinophilic inflammation may lead to structural esophageal changes (mural thickening, fibrosis) that might affect LES function and esophageal clearance Eosinophil products possibly render the esophageal mucosa more susceptible to injury by refluxed gastric juice
Eosinophils can also produce products that may alter esophageal motility that can induce reflux and can slow the clearance of refluxate. So, once the eosinophils arrive, they may help to perpetuate this process. Eosinophilic inflammation may lead to structural esophageal changes such as mural thickening and fibrosis. This might render the lower esophageal sphincter function not as good as it has been in its native state. Again, this is something that is speculative. We know that eosinophils can induce this kind of damage in lungs and other tissues where there is this type of inflammation, but it has not been shown to date. Finally, eosinophil products may, in fact, render that esophageal mucosa more susceptible to reflux gastric juices such as antigens or other noxious products or allergenic products that may induce perpetuating the inflammation.
16
Esophageal Eosinophilia
GERD contributes to esophageal eosinophilia
Acid-peptic damage to epithelial cells and their tight junctions could increase epithelial permeability
So, acid and peptic damage to epithelial cells and their tight junctions could increase permeability leading to these chronic changes.
17
Acid-Induced Production of Inflammatory Mediators by Human Esophageal Mucosa

N = 3 esophagi samples 9 8 PAF (ng/mg protein) 7 6 5 4 3 2 1 0 Tissue Supernatant HCl Control
(Data expressed as mean SEM)
Cheng L, et al. J Pharmacol Exper Ther. 2006;319:117-126.
Well, acid-induced production of inflammatory mediators has been shown in one basic study. In this study, the investigators utilized esophageal explants in which the muscularis was stripped, the esophageal lumens were tied off and were filled with hydrochloric acid, and then upon measurement of both the luminal contents, platelet-activating factor was shown to be both in the luminal contents, as well as the surrounding tissue, suggesting that acid could induce platelet-activating factor. Since platelet-activating factor has been associated with eosinophilic inflammation, this may be one of the mechanisms that eosinophils arrive into the esophagus.
18

Hydrochloric Acid (HCl) in Mucosa
Interleukin (IL)-1
Platelet-Activating Factor (PAF)
PAF released in esophageal circular muscle causes the sequential production of IL-6, H2O2, and IL-1 that, in turn, induces circular muscle to produce PAF
In fact, they went on to show that this platelet-activating factor containing supernatant could induce a number of different cytokines that could be produced by the muscular cells leading to esophageal dysfunction.
19

Hydrochloric Acid (HCl) in Mucosa
Interleukin (IL)-1
Platelet-Activating Factor (PAF)
PAF released in esophageal circular muscle causes the sequential production of IL-6, H2O2, and IL-1 that, in turn, induces circular muscle to produce PAF
HCl produces PAFs. PAFs attract and activate eosinophils. Release of PAFs by the esophageal mucosa initiates sequential formation of inflammatory mediators.
So, hydrochloric acid, indeed, may participate in this inflammatory response.
20
Eosinophils in the Esophageal Epithelium With Acid Suppression

Histologic Assessment of Esophageal Squamous Epithelium of 3 Patients, Pre- and Post-PPI Treatment
Feature (distance above gastroesophageal junction) Eos/high-power field (0-4 cm) Eos/high-power field (5-10 cm) Eos/high-power field (> 10 cm) Patient 1 (14 yrs)* Pre 37 6 Post 1 1 0
* Treated with omeprazole 10 mg twice daily Treated with omeprazole 20 mg twice daily Treated with omeprazole 20 mg daily
Ngo P, et al. Am J Gastroenterol. 2006;101:1666-1670.
Well, is there any clinical evidence to support the fact that acid, indeed, may produce a prompt and brisk eosinophilia? Last year, we had reported our findings of 3 patients who had esophageal-related symptoms that had been treated with proton pump inhibition. What you can see on the left-hand side of this slide are the eosinophils per high-power field 0 to 4 cm above the junction and higher. This is the pretreatment with proton pump inhibitor eosinophil counts. You can see they are 37 and 6. Following 2 months of proton pump inhibition, this patient had a histological remission.
21

Feature (distance above gastroesophageal junction) Eos/high-power field (0-4 cm) Eos/high-power field (5-10 cm) Eos/high-power field (> 10 cm) Patient 1 (14 yrs)* Pre 37 6 Post 1 1 0 Patient 2 (25 yrs) Pre 5 21 20 Post 3 3 0
The same findings were seen in the second patient who had 20 eosinophils,
22

Feature (distance above gastroesophageal junction) Eos/high-power field (0-4 cm) Eos/high-power field (5-10 cm) Eos/high-power field (> 10 cm) Patient 1 (14 yrs)* Pre 37 6 Post 1 1 0 Patient 2 (25 yrs) Patient 3 (9 yrs) Pre 5 21 20 Post 3 3 0 Pre 52 59 24 Post 0 0 0
and the same in a third patient who had up to 50 eosinophils per high-power field.
23
Eosinophils in the Esophageal Epithelium With Acid Suppression (cont.)

Feature (distance above gastroesophageal junction) Eosinophil aggregates Superficial eosinophils Basal zone hyperplasia Elongation of papilla Patient 1 (14 yrs)* Pre No Yes Yes No Post No No No No Patient 2 (25 yrs) Patient 3 (9 yrs) Pre No No Yes Yes Post No No Yes No Pre Yes Yes Yes Yes Post No No No No
Three patients present with dysphagia, food impaction, and vomiting Endoscopic features include white exudates and linear furrows, suggesting allergy-induced esophagitis
Importantly, the associative findings that are typically associated with eosinophilic esophagitis, including eosinophil aggregates, superficial layering of eosinophils, and basal zone hyperplasia as shown in each one of the patients had deep diminution or were lost following the proton pump inhibition. So, these were the findings in 3 children; and just in the last month Stuart Spechler has published another set of adult patients who had very similar features in an article termed The 20th Eosinophil. I think again he emphasizes the fact that eosinophilic inflammation is not just due to 1 disease, that we are looking at a different type of phenotype now that will be described over the next several decades.
24
Eosinophils in Allergy Injury: Evidence for Allergy-Inducing Esophageal Eosinophilia
So, what is the evidence that eosinophils, in fact, may be related to an allergic injury? Well, much of the data and much of the support from this comes from clinical trials in the sense of treatment.
25
Eosinophilic Esophagitis in Children:

Pharmacologic Versus Dietary Therapy
381 pediatric patients over 10-year period (66% male, mean age 9.1 3.1 years)
Liacouras CA, et al. Clin Gastroenterol Hepatol. 2005;3:1198-1206.
Chris Liacouras has the largest group of patients that he has followed now for over 10 years. He reported this 2 years ago and has experience with 381 patients, children, who had eosinophilic esophagitis.
26

Pharmacologic Versus Dietary Therapy
381 pediatric patients over 10-year period (66% male, mean age 9.1 3.1 years) Pharmacologic Therapy
40 35 30 Number of eosinophils 25 per high-power 20 field 15 10 5 0 Systemic steroids (n = 39) Topical steroids (n = 17) Cromolyn
0.9 33.5 28.7 27.7 23.5 28.3 25.4 27.6
Before treatment 4 weeks into treatment 6 months off treatment
11.2
(n = 14)
Shown here is the response in the sense of numbers of eosinophils per high-power field on the Y-axis to a number of different types of agents that should induce remission in allergic disease, including systemic steroids. You can see there is a marked diminution of eosinophils with topical steroids, again the same finding. But, when patients were to go off of these type of steroid preparations, there is a significant increase in the eosinophils, suggesting the necessity for a persistent immunomodulatory approach. Cromolyn, in the sense of Gastrocrom, was not effective in this. The reasons for this could be certainly multiple in the sense of lack of adherence of the medication to the esophageal mucosa. We still do not know exactly the role of mast cells in these diseases. So, this suggests, because of the pharmacological approach, in the sense of steroids, that there is an allergic etiology.
27

Pharmacologic Versus Dietary Therapy (cont.)
Food elimination diet (exclusion of certain foods based on skin prick or skin patch allergy test) Complete dietary elimination using only an amino acidbased formula (if allergy testing did not identify a specific food allergy)
The second line of evidence that suggests an allergy may play a role in this is the role of dietary therapy in the treatment of patients who have EE. We know that food elimination diets, as well as the use of amino acidbased formula, can induce a remission in most patients.
28

Prediet Eosinophils per 40 HPF GER symptoms (n = 134) Dysphagia symptoms (n = 30) Eosinophils per 40 HPF GER symptoms (n = 54) Dysphagia symptoms (n = 21) 38.7 10.3 134 30 Food Elimination Diet (n = 75) 47.5 12.1 54 21 5.3 2.7 2 1 < 0.001 < 0.01 < 0.01 Postdiet 1.1 0.6 3 1 P value < 0.001 < 0.01 < 0.01 Amino AcidBased Formula (n = 160)
These are the findings from Chris studies in which he showed that the use of an elemental formula or food elimination diet can induce a prompt histological response. So, here are the prediet numbers of eosinophils, the symptoms, and the symptom score, as well as dysphagia prediet and postdiet with the use of a food elimination diet, as well as an amino acidbased formula,
29

Prediet Eosinophils per 40 HPF GER symptoms (n = 134) Dysphagia symptoms (n = 30) Eosinophils per 40 HPF GER symptoms (n = 54) Dysphagia symptoms (n = 21) 38.7 10.3 134 30 Food Elimination Diet (n = 75) 47.5 12.1 54 21 5.3 2.7 2 1 < 0.001 < 0.01 < 0.01 Postdiet 1.1 0.6 3 1 P value < 0.001 < 0.01 < 0.01 Amino AcidBased Formula (n = 160)
CONCLUSION: Removal of dietary antigens significantly improved clinical symptoms and esophageal histology in 98% of patients
suggesting that if you were able to remove the offending allergen that you could get reduction in the number of eosinophils.
30
Effect of 6-Food Elimination Diet on Pediatric Eosinophilic Esophagitis Patients

Retrospective observational study assessed short-term clinical and histologic responses of 2 cohorts of children with eosinophilic esophagitis 6-Food Elimination Diet (SFED) excludes cow milk protein, soy, wheat, egg, peanut, and seafood Elemental Diet (ELED) crystalline amino acidbased diet
Kagalwalla AF, et al. Clin Gastroenterol Hepatol. 2006;4:1097-1102.
So, Amir Kagalwalla took a different approach to this treatment, and he said that really the difficulty in identifying the exact allergen is very significant. So, lets just take all of the most common food allergens, the 6 most common foods that can cause an allergic response, out of the diet and see what happens to the patients. He performed a retrospective observational study comparing patients who had 6 foods eliminated to those who were treated with an elemental diet.
31

Significant improvement Partial improvement Treatment Failure
(11-20 eosinophils per HPF) (> 20 eosinophils per HPF)
( 10 eosinophils per HPF)
Type of diet SFED
N (%) 26 (74%)
Peak Eosinophil* 3.1 3.2
N (%) 3 (9%)
N (%) 6 (17%)
Prebiopsy exam (peak eosinophil count) 80.2 44.0
Postbiopsy exam (peak eosinophil count) 13.6 23.8
P value
35
< 0.0001
Kagalwalla AF, et al. Clin Gastroenterol Hepatol. 2006;4:1097-1102.
The results are shown here. So, the type of diet is shown on the far left-hand slide. This is the side of the slide, the 6-food elimination diet. Importantly, you can see that this is divided into 3 different sections, so that these are greater than 10 eosinophils, partial improvement with 11 to 20, and then treatment failures of greater than 20 eosinophils per high-power field. There is the prebiopsy count and the postbiopsy count. The bottom line from this was that approximately 75% of patients who had 6 foods eliminated from their diet, indeed, went into both clinical, as well as histological remission.
32

Significant improvement
(11-20 eosinophils per HPF) (> 20 eosinophils per HPF)
Partial improvement
Treatment Failure
( 10 eosinophils per HPF)
Type of diet SFED
N (%) 26 (74%) 22 (88%)
N (%) 3 (9%) 2 (8%)
N (%) 6 (17%) 1 (4%)
Prebiopsy exam (peak eosinophil count) 80.2 44.0
Postbiopsy exam (peak eosinophil count) 13.6 23.8
P value
35
< 0.0001
ELED
25
1.6 2.1
15.0 2.8
N/A
58.8 31.9
3.6 6.5
< 0.001
* Peak eosinophil count: mean for the group SD of each group Kagalwalla AF, et al. Clin Gastroenterol Hepatol. 2006;4:1097-1102.
This was compared to the elemental diet shown here. The same kinds of findings were shown, except there were approximately 88% of patients who ended up going into histological, as well as clinical remission. So, again, suggesting that the removal of specific allergens that could be associated with eosinophilic inflammation induces a remission, supporting a role for allergens.
33
Summary
The interaction between GERD and eosinophilic esophagitis in pediatric patients is complex Food allergies are contributory factors in many children with eosinophilic esophagitis A diagnosis of eosinophilic esophagitis should be reserved for patients with characteristic endoscopic and histologic features who are unresponsive to PPIs Future studies will determine more about the etiologies leading to esophageal eosinophilia
So, to summarize, the interaction between GERD and eosinophilic esophagitis in pediatric patients is going to be complex. I think it is complex now in our daily care, but I think we are going to see even more complexities in the future. Food allergies are, indeed, contributory to many of the patients who have EE. A diagnosis of EE should be reserved for patients who have characteristic endoscopic and histological features who are not responsive to proton pump inhibition, and future studies will be needed to determine more about the etiologies leading to esophageal eosinophilia. Thank you.
34
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Controlling Esophageal Disease in Children Beyond the Acid

An Overview of Esophageal Disorders in Children

First, an overview of esophageal disorders in children.

Current Controversies in GERD and Esophageal Disease

So first, an overview of GERD.

GERD as a Chronic Disease

* Presented for medical attention

GERD Pathophysiology: A Motility Disturbance Leading to Esophageal Damage

Adapted from Jadcherla SR, et al. Am J Med. 2001;111(suppl 8A):64S-68S.

Overview of GERD Treatments

Tipnis NA, et al. Curr Treat Options Gastroenterol. 2007;10:391-400.

Pharmacotherapy Options for GERD

Side effects of anxiety, tremors, and dystonia

Risk of cardiac arrhythmia No longer available

Not available without IND

Neurological side effects including drowsiness and weakness

Pharmacotherapy Options for GERD (cont.)

What Role Does Nonacid Play in the Pathogenesis of GERD?

Esophageal pH Levels Determine Type of Reflux

Weakly acidic reflux Weakly alkaline reflux (nonacid)

Sifrim D, et al. Gut. 2004:53:1024-1031.

Agents Targeting Lower Esophageal Sphincter Relaxations

Efficacy of Baclofen in Children by Accelerating Gastric Emptying*

Placebo Group Gastric Emptying

Omari TI, et al. J Pediatr. 2006;149:468-474.

Overview of Esophageal Diseases in Children

Audience Question Results

Waterbrash Dysphagia Regurgitation Odynophagia All of the above

Esophageal Motor Dysfunction

Secondary Motor Disorder: motility dysfunction caused by a systemic or local condition

Common presenting symptoms of esophageal motor disorders:

Primary Esophageal Motility Disorders

Arora AS, et al. Curr Gastroenterol Rep. 2001;3:191-199.

Secondary Esophageal Motility Disorders

Chronic Idiopathic Intestinal PseudoObstruction

Secondary Esophageal Motility Disorders (cont.)

Esophageal Crohns Disease

Other Esophageal Disorders in Children

Eosinophilic Esophagitis Can Mimic GERD

Eosinophilic Esophagitis Can Mimic GERD

Consider eosinophilic esophagitis when GERD symptoms not responding to PPIs

Please click Continue to proceed to the next section

The Role of Nonacid and Acid Reflux in GERD

Samuel Nurko, MD, MPH

Role of Acid in Pediatrics

Percent of total time pH < 4

Mild to moderate esophagitis

Orel R, et al. J Pediatr Gastroenterol Nutr. 2003;36:266-273.

Effect of Omeprazole on Children With Erosive Esophagitis

80 60 44 40 20 0 Healed with 0.7 mg/kg/day

Healed with 1.4 mg/kg/day

Healed with 3.5 mg/kg/day

Hassall E, et al. J Pediatr. 2000;137:800-807.

Effect of Omeprazole on Symptoms in Children With Esophagitis

Percent of patients with moderate to severe symptoms

Pre-entry 5-14 days 3 months

Hassall E, et al. J Pediatr. 2000;137:800-807.

Effect of Lansoprazole on GERD Symptoms in Children

Nonerosive, 15 mg once daily (n = 64) Esophagitis, 30 mg once daily (n = 23)

Median days with GERD symptoms (%)

Fiedorek S, et al. J Pediatr Gastroenterol Nutr. 2005;40:319-327.

Efficacy of Lansoprazole on Extraesophageal Symptoms in GERD

Percent of children with improvement in symptoms

Does Acid Explain Everything?