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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 Children…Beyond 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.

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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 reflux–associated 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.

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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.

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with now 3 PPIs FDA approved for the pediatric population. 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.Current Controversies in GERD and Esophageal Disease • Many acid suppression options are available. 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. 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? 4 . 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.

Overview of GERD So first. an overview of GERD. 5 .

. older children • High incidence1 − 0. and it seems to go up with increasing age.52:457-462.91 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 2 • Treatment aimed to prevent mucosal damage. how do we learn how to transition these patients once they hit adolescence into adults and are cared for by our adult colleagues? Finally.99:806-812. 2007. and treat atypical manifestations * Presented for medical attention DK. J Pediatr Gastroenterol Nutr. et al.35:334-338. et al. et al. 3El-Serag HB. 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. et al. True populationbased incidence and prevalence studies have not necessarily been done. 4Waring JP. J Pediatr. I think an important area where research really needs to head are longitudinal studies. Clin Gastroenterol Hepatol. while having somebody of repute like Dr. but there are a number of papers presented at this meeting that do provide some more recent data. 2002. 2007. 2Hassall E. control symptoms. et al. Castell here from the adult side. Dig Dis Sci. Am J Gastroenterol.GERD as a Chronic Disease • Frequent: infants vs. 2007.150:262-267. 5Young RJ. 2004. 1Chitkara Reflux-related disease—and I do not need to tell you all this—is frequent in infants and in older children. prevent complications.5:186-191. 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. In particular.

a 15-year-old. decreased lower esophageal sphincter (LES) pressure leads to reflux PRIMARY MECHANISM 2: Impaired esophageal clearance. This slide here really highlights for you what is the overall pathophysiology. That is. which decrease at certain times and open inappropriately. Am J Med.111(suppl 8A):64S-68S. Sudarshan Jadcherla from Columbus Children’s 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. The same mechanisms in a 1-month-old with true GERD. a 5-year-old. et al. and then secondarily. impaired esophageal clearance of acid refluxate. or an almost 50-year-old with GERD are existing in patients with this entity. acid sensitivity. So. primary mechanism being transient lower esophageal sphincter relaxations. 7 . it is a motility-related disorder.GERD Pathophysiology: A Motility Disturbance Leading to Esophageal Damage PRIMARY MECHANISM 1: Transient lower esophageal sphincter relaxation (TLESR). 2001. inhibited peristalsis Adapted from Jadcherla SR. I think what is exciting standing before you tonight is that now there are some data in children.

Gold) There is a good short answer. Gold) Dr. (Dr. just beware you may be called upon. Do we have consensus here? Somebody else that wants to offer some other… (Dr. so talk amongst yourselves. Gold) So. GERD is a motility disorder.Audience Interaction • If GERD is a motility disorder. There are other medications such as baclofen that affect the lower esophageal sphincter. (Dr. Teitelbaum has an answer here. Furuta and Dr. and why do we have so few promotility agents available? This is a team effort. Colletti. Nurko) Yeah. but so few promotility agents? So our first team question to address. One more response and then we need to move on. are you ready to ask a particular team? (Dr. 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. (Dr. why are there so many acid suppressing agents that are available and are effective in the majority of patients with GERD. why do we have many acid suppression options. 8 . So again. but the effector of the damage is acid. Colletti) We have them but they don’t work. side effects. it is so good to see you this evening. and since they know some of you. we have them but they do not work. (Dr. (Dr. Dr. Nurko. So discuss amongst yourselves for the next couple of minutes what you think the answer to this particular question might be. and when you try to affect the GI nerves then you end up affecting the nerves of other organ systems. … Here. I think we are ready. and Drs. and then they get pulled from the market. but so few promotility agents? If it is a motility-related disorder. 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. Furuta) Dr. we have a volunteer. Nurko and Furuta are now rounding the audience. being pulled from the market.

10:391-400. Nurko and Castell. particularly Drs. including the convener of those revised guidelines. that they are about three-quarters to 85% through. and then often times after they failed. 2007. sucralfate) • Gastrointestinal prokinetic agents (eg. I think we would all agree. domperidone. Nissen) • Enteral feeding device • Esophagogastric dissociation Tipnis NA. and that was in the first GERD guidelines published by our society and endorsed by the American Academy and the revised GERD guidelines. and surgical methodologies that are used.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. The bottom line is that we use the nonpharmacologic or conservative methodologies whether or not we use pharmacologic or surgical therapy. This slide—and for the sake of time I will not go through it for you—highlights some of the nonpharmacologic. during the course of the presentation. Curr Treat Options Gastroenterol. et al. pharmacologic. I am told by a very reliable source. we go to fundoplication. Actually. baclofen) • Acid-suppressive agents (H2RAs. 9 . sodium alginate. Once we have decided that the child or infant or adolescent does not respond we go to pharmacologic management. you will hear some thoughts and data actually with respect to the role of fundoplication. PPIs) Surgical • Fundoplication (ie. which should be published actually within the next year.

placebo-controlled trials. metoclopramide. Thomson PDR. In 6 randomized. Baclofen actually does have some potential role. et al. J Pediatr. tremors. Bethanechol actually does have some potential use.146(3 suppl):S3-S12. 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. sweating. side effects. and adults • Evidence suggests poor clinical efficacy Motility Agents – – Metoclopramide • Side effects of anxiety. individual clinician discretion is necessary when using these agents for treatment of GERD Hassall E. as well as domperidone. and proven risks with all of these agents. Physicians’ Desk Reference. particularly looking at GABA receptors and agents that might have some activity on that aspect of esophageal disease.10:391-400. 2007. the list of those that were players. not one except for that which used pHmetry. are shown on this particular slide. and dystonia Bethanechol • Side effects (dizziness. was there a clinically evident benefit from those medications. Tipnis NA. children. 10 .Pharmacotherapy Options for GERD Therapy Considerations • Available for infants (limited data). Castell. 2007. 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. As you can see with the top one. With respect to motility agents. and there is some data that will be presented by Dr. Montvale. vomiting. and it is an exciting area with respect to the motility-related field. Curr Treat Options Gastroenterol. NJ. are no longer players. 2005.

adolescents. 11 . Thomson PDR. 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. Montvale.146(3 suppl):S3-S12. and adults – Solution or suspension forms and effervescent tablet • Less potent acid suppression compared with PPIs • Tachyphylaxis (ie. 2007. For sake of time again.) Therapy Histamine2Receptor Antagonists (H2RAs) Considerations • Available for infants (ranitidine). et al.10:391-400. tolerance) is an issue • Lansoprazole and omeprazole available for children. J Pediatr.Pharmacotherapy Options for GERD (cont. NJ. 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. Curr Treat Options Gastroenterol. 2005. Physicians’ Desk Reference. Suffice it to say there are 4 H2 blockers that are approved for pediatric patients and 3 PPIs that are FDA approved. children. 2007. Tipnis NA. lansoprazole. and omeprazole. esomeprazole.

12 . which will go into this in more detail. a couple of definitions for you.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.

13 . So acid reflux is reflux of gastric contents. et al. Weakly acid reflux. occurs when the esophageal pH is between 4 and 7.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. Gut. which is also termed nonacid reflux. 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. and then weakly alkaline reflux or true nonacid reflux is when the pH does not drop below 7. 2004:53:1024-1031.

drowsiness.149:436-438. somatostatin—or those that increase LES relaxation. 2006.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. like that last comment. dizziness. fatigue. 14 . and to lower threshold for seizures Di Lorenzo C. ondansetron. Now there are a number of agents that target the lower esophageal sphincter relaxations. atropine. J Pediatr. baclofen. I think it is a very exciting area in which a lot of research is now ongoing in clinical trials. baclofen has been shown to reduce acid and nonacid reflux • Baclofen is known to cause dyspeptic symptoms. Shown on this slide are a list of those agents that either decrease LES relaxation—so a medication. such as cholecystokinin or nitric oxide.

1† Session 2 (received baclofen) 61 (47.149:468-474.2† * Randomized. This is a particular study that looked at baclofen to accelerate gastric emptying. 91) (P = 0. 12 female. The cohort size was 30. 170)† 86 (70.077) 3.3 ± 0. You will see the breakdown.2 ± 0. and then a baclofen group. The bottom line was that this medication actually did accelerate gastric emptying.Efficacy of Baclofen in Children by Accelerating Gastric Emptying* Placebo Group Gastric Emptying Session I (received baclofen) 61 (39. 77)† Gastric Emptying t ½ (min) Gastric Emptying tmax (min) Gastric Emptying Coefficient 3. 81) 56 (48. 95)† 66 (51. et al. 84)† 68 (56. whether it was looking at a time for gastric emptying or gastric emptying coefficient. placebo-controlled trial N = 30 (18 male. placebo-controlled trial in children. mean age 10. double-blind. this is a particular study. 12 female.0 ± 0.05 Omari TI.3 ± 0. 108)† Baclofen Group Session 1 (received baclofen) 71 (33. and the median age was about 10 years of age. 73) Session 2 (received placebo) 114 (67. With respect to gastric emptying. 2006. J Pediatr. 15 . 18 male.8 years) †P < 0.2† 3.8 ± 0. Now I am going to focus on the gastric side of it. double-blind. and then Drs. Castell and Nurko will talk about the esophageal side. and they had 2 sessions.1 2. There was the placebo group. and as you can see this was actually a randomized.

16 .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.

All of the above 17 . 5. Dysphagia 3. Waterbrash 2. The question is as follows. 2. 3. 4. so take your keypads now. Common presenting symptoms of an esophageal motor disorder include? You have 5 choices: 1. Regurgitation 4. Waterbrash Dysphagia Regurgitation Odynophagia All of the above The first audience response question. Odynophagia 5.Audience Question • Common presenting symptoms of an esophageal motor disorder include? 1.

. 5% regurgitation. The audience is very clued in to what we have here. 7% dysphagia. Very good. Next slide please. and I am not going to further discuss the answers. 82% all of the above.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.

and the definitions are shown on this slide. Shaffer EA. diffuse esophageal spasm. or even eosinophilic esophagitis. Mayrand S. 3rd ed. Watkins JB. Management. Other neuromuscular disorders. Walker-Smith JA.Esophageal Motor Dysfunction • Primary Motor Disorder: usually affects the esophagus alone and often has no known etiology – Examples: nutcracker esophagus. Gold B. Secondary motor disorders are motility dysfunction that is caused by something else. Ottawa: Canadian Public Health Association. eds. with respect to esophageal motor disorders. eds. First Principles of Gastroenterology: The Basis of Disease and an Approach to Management. So first. they are broken down into primary and secondary. either a systemic or a local condition. The esophagus. Crohn’s disease. Durie PR. Crohn’s esophagitis • Common presenting symptoms of esophageal motor disorders: − Dysphagia − Nonheartburn chest pain − Bleeding − Regurgitation − Heartburn/pyrosis − Waterbrash − Respiratory/laryngeal symptoms − Odynophagia Paterson WG. achalasia • Secondary Motor Disorder: motility dysfunction caused by a systemic or local condition – Examples: esophageal atresia/tracheoesophageal fistula. Pediatric Gastrointestinal Disease: Pathophysiology. In press. In: Thomson ABR. Diagnosis. In: Walker WA. Examples are shown there. 19 . Examples are diffuse esophageal spasm and achalasia. and they actually can be things like esophageal atresia and tracheoesophageal fistula. 1997:88-128. Primary motor disorders of the esophagus usually affect the esophagus alone and often have no known etiology. Hamilton JR. Common presenting symptoms as you all correctly—or 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.

and the next 2 slides are going to focus on these. and then what used to be called nonspecific motility disorder but now actually—and you will see some data in more detail in Dr. Curr Gastroenterol Rep. diffuse esophageal spasm. are grouped into the following: achalasia. Primary motor disorders. absence of peristalsis in the smooth muscle component of the esophagus. which can be caused by an infectious agent. where it is characteristic of primary achalasia. et al. 2001. Castell’s talk—ineffective esophageal motility.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. and elevation consistent of intraesophageal baseline pressure and incomplete LES relaxation. Nurko’s and Dr. 20 .3:191-199. and then secondary.

In: Walker WA. Walker-Smith JA. Durie PR. Diagnosis. of Barrett’s esophagus and even adenocarcinoma in these patients. In terms of secondary esophageal motility disorders. In press. Chronic idiopathic intestinal pseudo-obstruction. Management.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. something which happens in 10%20% of children in the United States. 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. at least based on 2000 CDC data. We have absolutely no guidelines. esophageal atresia or tracheoesophageal fistula. Watkins JB. abnormal peristalsis and impaired LES function. Other neuromuscular disorders. Pediatric Gastrointestinal Disease: Pathophysiology. Hamilton JR. eds. 21 . can also affect the esophagus. and in fact in longitudinal studies there have been 3 papers published just in this past year. because it is cross section. can also cause a secondary motility disorder. and then caustic ingestion. which tends to primarily occur in the midgut and colon. which actually looked at the incidence or prevalence if you will.

Diagnosis. can also cause a motility disorder. Furuta’s section. Other neuromuscular disorders. eds. and then esophageal Crohn’s disease.) 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 Crohn’s Disease Gold B. In: Walker WA. which we will talk about in much more detail in Dr. Pediatric Gastrointestinal Disease: Pathophysiology. Hamilton JR. Management. 22 .Secondary Esophageal Motility Disorders (cont. Durie PR. Walker-Smith JA. In press. Watkins JB. Eosinophilic esophagitis.

Other Esophageal Disorders in Children Other esophageal disorders that you have to consider in terms of motor disorders 23 .

pylori over the last 20 years. The esophagus. 3rd ed.. First Principles of Gastroenterology: The Basis of Disease and an Approach to Management. Then to transition into that. which we are seeing a lot more. Crohn’s esophagitis. Ottawa: Canadian Public Health Association. foreign bodies. pylori of the 2000s. congenital malformations. In: Thomson ABR. I think this is at least one of those who I would say I am a “helicophile” being an interest in H. and then eosinophilic esophagitis. caustic ingestions. this is the H. 24 . Mayrand S. Shaffer EA. and the differential would be an infectious esophagitis and complications of bone marrow transplants.Differential Diagnosis • Infectious esophagitis • Complications of bone marrow transplants • Crohn’s esophagitis • Foreign body • Congenital malformations • Eosinophilic esophagitis Paterson WG. particularly at hospitals that have busy BMT services. eds. 1997:110-111.

as in many of the esophageal disorders.4% of children with reflux-related symptoms. almost 7% of children with esophagitis. vomiting. 2004. population-based studies have not been done but clearly in single-center studies. odynophagia. the Y chromosome is the weaker link. So prevalence estimates range from 3. eczema. 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. heartburn. regurgitation. Male predominance 70% to 80% of cases. and 20% of children with dysphagia. food impaction. Clin Gastroenterol Hepatol. abdominal and chest pain. 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.Eosinophilic Esophagitis Can Mimic GERD • • “Allergic esophagus” – is the prevalence of this disease or physician awareness increasing? Prevalence estimates – 3. Arora AS. et al. et al. food impaction. whether it is ingested food allergens or both.133:1342-1363. Again.2:523-530. Signs and symptoms can range from dysphagia. food allergy Furuta GT. 2007. and there is often a family or personal history of atopy and allergy. abdominal/chest pain. Clinical features. whether it is aeroallergens. I think is an important issue. 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. 25 . Gastroenterology. the overall prevalence seems to be increasing as is the numbers of papers published in parallel.4% of children with reflux symptoms – 6. vomiting.8% of children with esophagitis – 20% of children with dysphagia • Signs/symptoms – Dysphagia. rhinitis. and feeding refusal.

et al. and you will see how that fits nicely in the next 2 talks. 26 . Gastroenterology. 2004. Clin Gastroenterol Hepatol.133:1342-1363. vomiting.2:523-530. food allergy Furuta GT. odynophagia. heartburn. Arora AS.4% of children with reflux symptoms – 6. eczema.Eosinophilic Esophagitis Can Mimic GERD • • “Allergic esophagus” – is the prevalence of this disease or physician awareness increasing? Prevalence estimates – 3. rhinitis.8% of children with esophagitis – 20% of children with dysphagia Consider eosinophilic esophagitis when GERD symptoms not responding to PPIs • Signs/symptoms – Dysphagia. 2007. 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. abdominal/chest pain. et al. regurgitation. So consider esophagitis when GERD symptoms are not responding to PPIs. food impaction.

and eosinophilic esophagitis. primary or secondary. eosinophilic esophagitis) • GERD is a motility disturbance. Crohn’s esophagitis. Therapy is therefore targeted against the effector of the esophageal and extraesophageal inflammation. and yet there is a shortage of treatment options available with efficacy that affect LES function and esophageal body peristalsis. 27 . motor dysfunction. esophageal disease presents in many forms ranging from motor dysfunction. infectious esophagitis. with 1 second left and we will move over to our next 2 presentations. and that can keep people in remission from pediatric patients with simple nonerosive esophagitis with erosive esophagitis to adults with Barrett’s esophagus. GERD is a motility-related disorder where the effector of the damage is acid. Crohn’s disease. 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. We have good agents that are on the market that can heal symptoms. that can heal the mucosa. infectious esophagitis. But.Summary • Esophageal disease presents in many forms (eg. 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. Most GERD responds to acid suppression.

Please click “Continue” to proceed to the next section Continue .

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 Children’s 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.

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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.

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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.

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2000. the symptoms really decrease. What about symptoms? There are studies with different PPIs.137:800-807. et al. 4 . This has been replicated with other PPIs. and you can see when you take patients that have GERD and evidence of esophagitis and you give them an acid suppressing agent. J Pediatr. 3 months in red. This is the same study from Eric (Hassall) in which you can see how the symptoms decrease over time. 5-14 days in yellow.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.

15 mg once daily (n = 64) Esophagitis. 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. 2005. 30 mg once daily (n = 23) P < 0. J Pediatr Gastroenterol Nutr.Effect of Lansoprazole on GERD Symptoms in Children 100 90 91 85 Nonerosive.001 vs. . You can see very similar effect and actually even in atypical symptoms. This is a study with lansoprazole.40:319-327.

J Pediatr Gastroenterol Nutr. 35(suppl 4):S308-S318. 6 . 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. et al. So I think that what we know is that when acid production is blocked or neutralized with the use of medications. 2002.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. You can see that atypical symptoms associated with reflux also respond to gastric acid suppression.001 Tolia V.

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? 7 . and maybe that is the reason you are here. many patients continue with symptoms despite aggressive medical therapy. have normal pH probes. as all of us know.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. 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. and experience dramatic improvement in their symptoms after fundoplication • Are we missing something? However.

4. MII. Endoscopy pH monitoring Wireless pH monitoring Multichannel intraluminal impedance So this is another audience question that I’m going to pose to you. Endoscopy 2. or multichannel intraluminal impedance Again. 8 . pH monitoring 3. there is no right or wrong answer.Audience Question • I utilize the following test most often for children with persistent GERD symptoms who are unresponsive to acid suppression treatment: 1. I utilize the following test most often for children with persistent GERD symptoms who are unresponsive to acid suppression treatment: 1. 2. Wireless pH monitoring or BRAVO™ 4. 3.

I just want to press upon the fact that probably Glenn is going to touch on that. I think impedance is one of the techniques that is being used more. You can do it with and without treatment and have some advantages. would do endoscopy. but if you are completely blocked. Wireless pH monitoring is a new technique. Finally. Most people in the audience. The pH monitoring. It is good because you can do it for 3 or 4 days so it has advantages. 65%. . It is very important to do this after the patients have had a very good PPI treatment. has limitations. as we are going to talk about later. it can be useful. Most people do it for 2 days. I am going to try to put these techniques in perspective during the talk today. the pH monitoring is going to miss every reflux that is not acid. and if you are not completely blocked.Audience Question Results • 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. and I suspect that is because you want to exclude the presence of eosinophilic esophagitis.

We also have what is called relation to symptoms. and I am not going to dwell too much on it. What are the limitations of pH monitoring? We clearly lack … there is a lack of sensitivity and specificity that is very well described. Aliment Pharmacol Ther. Most of us do not do manometry. 2005:22(suppl 3):2-9. 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 . electron positioning is a problem.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. 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. but there is also displacement. Most of the kids we do the pH probe on do not go to school and do not do sports. not everything is acid exposure. pepsin)? • To address the limitations: – Wireless pH monitoring – Impedance monitoring and pH – Other methods Kahrilas PJ. but we know that this is related to reduced patient’s physical and dietary activity. and we either use the total formula or we use the NASPGHAN criteria. and in pediatrics we never know exactly where we are. so depending on where your catheter is and how it is facing. et al. the question. You have variability in acid exposure. Now.

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

2005:41:411-415. What this shows you is that if you compare the first day with the second day. You can see the age here.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. It revealed that the overall reproducibility of a single 24-hour period was 77%. reported some degree of discomfort during the study.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. however. is that most of the patients. The data analysis was very good.Tolerability and Reliability of Wireless pH Monitoring in Children • 44 children (27 males. but it was close to 80%. 12 . 17 females) – Mean age 11. it is not 100%. 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. The authors erred on the side that if there was conflicting evidence they always erred on the side of diagnosing reflux. et al. What they did have. There was no significant difference between the 2 days when you were trying to compare both. 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. The pain was really generally mild. J Pediatr Gastroenterol Nutr. but there was also a sensation of a foreign body. 68%.

so it allows you to decide if you are having reflux if the reflux is acid or nonacid. Gastroenterology. How does impedance work? Impedance is measuring electrical resistance between electrodes. or alkaline reflux. 2007. et al. so it allows you the evaluation of the nature of the refluxate that you have.Measuring Reflux by Multichannel Intraluminal Impedance • Detects both acid and nonacid reflux – Acid reflux = drop in pH below 4. Now. Given that it is not pH dependent. 2001.10:391-400. 13 . 2001. It always is done with an attachment of a pH meter. Sifrim D.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. Ben already showed you the definitions. it is flow dependent. You can see if you have liquids. the problem with the BRAVO™ and the pH probe is it does not address the fact that not all reflux is acid. which is to 4 to 7. if you have gas. Curr Treat Options Gastroenterol. You can have weakly acidic within the nonacid reflux. et al. You have acid reflux when you drop below 4 and nonacid reflux when it is above 4. that is why the technique is combined.120:1588-1598. if you have mixed reflux. et al. The advantage in the advent of the impedance or MII is that it can detect both acid and nonacid reflux.120:1599-1606. Tipnis NA. Gastroenterology.

2007. so you can see how the impedance changes. You have a pH that does not show very well that is measuring the reflux. Eventually. If air goes through the 2 electrodes. and Don is going to show you more information of these. You have the electrodes. Air has very high resistance. This is just a schematic example. et al.20:83-88. the drop is even more. If you use things like saline or things with electrolytes. The impedance changes with the different substances you have in your esophagus. . where you are measuring the electrical resistance. it recovers.Impedance Wave Air preceding bolus Liquid bolus Recovery Ohms Based on changes in resistance to electrical current Time Wise JL. Liquids have decreased resistance. Dis Esoph. you can see there is a big upward curve.

Dis Esoph. the bolus is going down. by doing this. So. the impedance is going to decrease. and then you can see that depending on what is happening you are going to see impedance changes. the resistance between each one of the pairs is going to be measured. if the liquid is going from the stomach up into the mouth. . you can see how it starts distally at this level and it goes up to the mouth. if you have a series of electrodes at different parts. On the other hand. it happens backwards. et al. 2007. in which you can imagine how the reflux is occurring and how the swallowing is occurring. and it is going to start from the upper electrodes to the lower electrodes. and you will see this pattern.Impedance Wave Air preceding bolus Liquid bolus Recovery Ohms Based on changes in resistance to electrical current Time Time Time Wise JL.20:83-88. So. if you are swallowing something.

16 . but you can measure 6 channels. MD. and you can actually measure the pH. This is how a real impedance tracing looks. liquid. We do not have time to really go into much. and allows you to decide if the reflux you are having is actually acid or nonacid. MPH. You can see the height of the reflux. This would be a typical nonacid reflux episode that would not be detected by a pH probe. This is the advantage of the impedance. you can see here is a reflux episode that is going retrograde. allows you to see what you have there. full column Impedance reflux episode Height Bolus clearance time (BCT) pH Image courtesy of Samuel Nurko. or mixed. gas. It allows you to see how high it goes.Representative Impedance Tracing: Nonacid Reflux Episode Nonacid.

Acta Paediatr.96:956-962. et al. 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.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 0 20 40 60 80 100 Percent of nonacid reflux episodes recorded (relative to total number of reflux episodes recorded) Vandenplas Y. These are all of the studies in pediatrics that have been published up to early 2007. This is a recent report by Yvan Vandenplas. 2007. 17 . I am not going to have time to go through this slide.

1 4 % Bolus exposure 0.4 pH-only REs 0 0.Comparison of Impedance in Prematures and Adults Adults Total 24 hours Median 25th. and Dr.5 6. We do know this is the normal data from Shay.3 Shay S. 1 3 pH % Acid exposure 1.5 0.3.99:1037-1043.9 1. . 2. 15 26 Nonacid 0 0.118:e299-e308. 0 1 Superimp acid 0 0. 75th 95th Percentile All Reflux Total 30 18. 2006. Castell was part of this. 0. 16 44 Frequency of Reflux Types Acid 18 7. 31 55 Weakly acid 9 6. Pediatrics.3. where you can see the normal events of reflux. 45 73 Duration(s) 10 6. Lopez-Alonso M. How do nonacid reflux events in children compare to adults? We have no data. et al. Am J Gastroenterol. et al. 2004.2 0.

2004. 0.4 52. which is related to the fact that the younger you are the more feedings you get in your stomach more frequently. of course these are preemie babies.4 pH-only REs 0 0. This is the only study we have in kids.59 20. 1 4 % Bolus exposure 0. et al. Pediatrics. Lopez-Alonso M.3. 75th 95th Percentile All Reflux Total 30 18. the reflux tends to be much more full column than in adults.5 6.17 Shay S.66 6. 16 44 Frequency of Reflux Types Acid 18 7.36 Total acid exposure % / 24 hours 5.3.9 1.99:1037-1043. 1 3 pH % Acid exposure 1. and they tend to have much more nonacid reflux. The only thing I want to point out. . 31 55 Weakly acid 9 6.7 % Acid reflux 25.3 Prematures Median 95th percentile Total reflux n / 24 hours 71 100.5 0. 2.118:e299-e308. 0 1 Superimp acid 0 0.3 Weakly acidic (%) 72.Comparison of Impedance in Prematures and Adults Adults Total 24 hours Median 25th. 45 73 Duration(s) 10 6. This is done in premature babies with an NG tube from Lopez-Alonso in Spain. 15 26 Nonacid 0 0.2 0. et al. 2006. Am J Gastroenterol.9 98 Reflux-related acid exposure % / 24 hours 1. they tend to have much more reflux episodes than adults.

16 44 Frequency of Reflux Types Acid 18 7.4 52. Lopez-Alonso M.3 Full column 36% Full column 90% Total reflux n / 24 hours 71 100. 0. 15 26 Nonacid 0 0.5 6. et al.36 Total acid exposure % / 24 hours 5. 0 1 Superimp acid 0 0. 1 4 % Bolus exposure 0.5 0.66 6. 2004.17 Prematures Median 95th percentile Shay S. however. et al.99:1037-1043.59 20. 2. 45 73 Duration(s) 10 6. Impedance cannot be used at this point to decide who is normal and abnormal. and that is one of the most important messages I would like to leave with you.118:e299-e308.9 98 Reflux-related acid exposure % / 24 hours 1. Impedance. and we do not know what the normal values are.7 % Acid reflux 25.9 1. So.3. 2006. 1 3 pH % Acid exposure 1.2 0. can be used to try to explain if the symptoms you see in the PPI-resistant patient are related to reflux or not. 31 55 Weakly acid 9 6.4 pH-only REs 0 0. Am J Gastroenterol. in between lies the rest of children. Pediatrics. We do not have this standard. which brings me to the next point. clearly.3. .Comparison of Impedance in Prematures and Adults Adults Total 24 hours Median 25th. 75th 95th Percentile All Reflux Total 30 18.3 Weakly acidic (%) 72.

82) 0.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 58.63 (0. liquid reflux. Am J Gastroenterol.8 Odds Ratio 0.31 (1. and respiratory symptoms.97) 1. So.01-1.70 (1.03-2. This is our own study.01 0.02 0.9 19.4 2. and the presence of nonacid reflux was most significant. Nonacid reflux.88 (0.92) 1. particularly if it was very high.69) P Value 0.00 (0. 21 . there was a good correlation between nonacid reflux. proximal height.00) 0. How long the reflux was in the esophagus was not significant. as compared to acid reflux. nonacid reflux is important in the association of symptoms with patients that are resistant to therapy.3 Percent of reflux episodes 70 60 50 40 30 20 10 0 Distal Mid Proximal 5. clearly.99:2452-2458.4 8. As you can see.98-1.42-0. This is just multivariate analysis to show you the same.79-0.04 1. 2004.8 75.36 Area of Esophagus Rosen R.04 0. et al.

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 .

So.29) 80. In patients that you do tests on treatment. Yes.2% ± 31. That is a very difficult question. 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. if you look at age. we can conclude that in the younger children impedance is probably better than a pH probe in an untreated patient. 2006.005 Sensitivity of pH Probe (P = 0. trying to analyze the sensitivity and specificity of both techniques.4% ± 17.0% 80.1% 71. you can see that in infants the sensitivity of the pH probe in untreated patients was much lower than the impedance. et al.3% 80. obviously because you are detecting more nonacid reflux. the sensitivity of the impedance is much higher.2% Sensitivity of Impedance (P = 0.2% ± 36. this has to do with the way we feed infants. Clin Gastroenterol Hepatol. but as you go from school-age to older kids there does not seem to be any difference in the sensitivity of the test.10) Infant (aged 0-2 years) Pediatric (aged 2-10 years) Adult (aged > 10 years) 49. you have more reflux.1% ± 33.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) 80.4:167-172. However.8% ± 11. This is our own data trying to compare patients with impedance and pH probe. particularly if you have symptoms.3% 77.6% ± 18. I do not have time to go through this.1% 0.1% ± 13.8% ± 25.5% P value 0.9% 63. but the question is does that mean that that is important? 23 .3% ± 21.5% Rosen R.2% MII 76.41 47.9% ± 31. Again.

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.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. 24 . we have a lot of patients that are continuously fed. Obviously. and that is a perfect indication for impedance.

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

Audience Question Results
• 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

We are doing some studies on this. 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 . proving causality is difficult Pediatric studies are needed to determine if knowing the amount of nonacid reflux changes treatment or outcome So. but that is the main question. clearly we know that we need pediatric studies to know also if the amount of nonacid reflux changes the outcome and treatment. and the data is going to come.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.

Treatment of Nonacid Reflux Surgery What are the treatments? There are 3 modalities: • Surgery. You know that is the best treatment. 29 .

Treatment of Nonacid Reflux Surgery Medications • You have medications that already were alluded to. 30 .

31 .Treatment of Nonacid Reflux Surgery Medications Other (jejunal feedings) • You can bypass the stomach and do something like jejunal feedings.

This is a study in which fundoplication was done in adult symptomatic people that had a positive symptom correlation with impedance. so I hope that by the time DDW comes I can actually give you data on how does impedance work in children with fundoplication.wikipedia. We have a study at Children’s that we are completing with about 30 patients with fundoplication. We do not have data in pediatrics about fundoplication. Br J Surg. I am just borrowing it from him. et al. 2007. http://en.org/wiki/Nissen_fundoplication. Image reproduced from Wikipedia Web site. 2006. Don Castell is going to show you his data.93:1483-1487.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. I am going to let him present his data. They show that it was very good. Accessed October 15. 32 .

149:468-474. there is 1 study uncontrolled in Japanese children in 9 kids with CP that it showed it was effective. 2006. Omari in Australia. et al. J Pediatr.0 ± 0.01 Omari TI.05 ‡ P < 0. 12 female.Efficacy of Baclofen in Reducing Incidence of TLESR and Acid Reflux* • Patients intubated with manometric/pH assembly and given 250 mL cow’s milk • Esophageal motility and pH measured for 2 hours (control period) • Baclofen or placebo administered • Measurements performed for another 2 hours (test period) * Randomized. Now regarding baclofen. but this is a landmark study from Dr.8 years) † P < 0. mean age 10. as you know. placebo-controlled trial. double-blind. N = 30 (18 male. 33 .

01 Omari TI. 2006.6 . N = 30 (18 male. What they did is they did a placebo-controlled study in which they gave baclofen and they measured baseline manometry.3 ± 0.4 1. +63%] (Data expressed as mean ± standard error of mean. or median [interquartile range]) * Randomized. placebo-controlled trial.8 years) † P < 0. mean age 10.149:468-474. double-blind. You can see the number of inappropriate relaxations.9 ± 0.6% [-38%. whether the relaxations gave you reflux or not.Efficacy of Baclofen in Reducing Incidence of TLESR and Acid Reflux* • Patients intubated with manometric/pH assembly and given 250 mL cow’s milk • Esophageal motility and pH measured for 2 hours (control period) • Baclofen or placebo administered • Measurements performed for another 2 hours (test period) Esophageal Motility and Acid GER Number of TLESRs % change Number of TLESRs + Acid GER % change Placebo Group Control Period 6.8 Test Period 5. 34 .9 ± 0.05 ‡ P < 0. 12 female.4 0% [-38%.0 ± 0. et al. J Pediatr.0 ± 0. -18%] 1.

mean age 10. -18%] 1.Efficacy of Baclofen in Reducing Incidence of TLESR and Acid Reflux* • Patients intubated with manometric/pH assembly and given 250 mL cow’s milk • Esophageal motility and pH measured for 2 hours (control period) • Baclofen or placebo administered • Measurements performed for another 2 hours (test period) Esophageal Motility and Acid GER Number of TLESRs % change Number of TLESRs + Acid GER % change Placebo Group Control Period 6. placebo-controlled trial. 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.2† .0 ± 0.6 Baclofen Group Control Period 7. and that has been the biggest limitation.75%]† (Data expressed as mean ± standard error of mean.8 Test Period 5. double-blind.6 ± 1.01 Omari TI.8 years) † P < 0.4 1. 12 female.67% [-95%.9 ± 0. N = 30 (18 male. +63%] .0 ± 0.83% [-100%.3 ± 1.3 ± 0.7‡ 1. . It has a lot of side effects.9 ± 0.6% [-38%.2 ± 0.0† 0% [-38%.05 ‡ P < 0. J Pediatr. et al. This is more a model of study. 2006. 35 . or median [interquartile range]) * Randomized. -33%]† 4. and they compared placebo with baclofen. as you know. Clearly. baclofen is something important.4 .7 ± 1.149:468-474.5 Test Period 3.

8 26.4 26.4 GERD patients Control patients N = 13 Number of events 50 40 30 20 10 0 18. this is the data we are presenting here. Maybe it is the amount of refluxate.4 10. and Control Patients 60 Jejunal feeding patients 47. Jejunal Feeding Patients. we will use J-tube feeds. Finally. J-tube feeds do not change the amount of reflux you have.4 13. 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.5 26. 36 .45(suppl 7):E40-E41. It is interesting.07) There were no differences between the heights and the total numbers of reflux events between GERD and jejunal feeding patients Rosen R.02) pH-only events (P = 0. I do not know exactly how J-tubes work. They do work. et al.7 7.003) Nonacid events (P = 0.9 51. I think our experience is that J-tube feedings really work in some of these children. Abstract 105. 2007.4 54.5 7. and to our surprise. J Pediatr Gastroenterol Nutr. these patients continue to need to be treated.04) Total MII events (P = 0. So. Impedance dosing lets you see if the volume is decreasing. We tried to see what was the effect of J-tube feedings on reflux.1 33.5 Acid events (P = 0.Comparison of Reflux Profiles: GERD Patients.

37 . and those with atypical symptoms • New therapies are needed Thank you.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.

Please click “Continue” to proceed to the next section Continue .

It is truly a pleasure to be here with you. South Carolina. at MUSC is going to talk about the role of nonacid and acid reflux in GERD from the adult perspective. Castell) Thank you Ben. if you will. Dr.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. Castell. Good evening everybody. 1 . The definition is an individual who makes a living out of heartburn. Dr. I have been doing this disease for 40 years. People call me an esophagologist. We are going to talk about what we esophagologists have done. I am really honored to be in the presence of and to listen to what you are about to hear. whereas most people get heartburn from making a living. Gold) So. we are moving on into the adult perspective. professor of medicine and director of the Esophageal Disorders Program and Digestive Diseases Center in Charleston. Don Castell. 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. SC Donald Castell. (Dr. MD (Dr.

but every one of you see patients today that are still having symptoms despite adequate acid suppression. 2 . that is the abnormal motility. the reflux mechanisms are not changed. the permissive lower esophageal sphincter.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. This is by and large an acid disease. we will talk a little bit about how we would probably treat these patients. therefore. 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. PPI therapy. it only changes the pH of the refluxate. why not?” We are going to address the fact that. How do we make the diagnosis? What is its prevalence? Is it clinically important? Bottom line. “Of course. yes. 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. The role of acid is well established. So. the question that has arisen over the last decade is could these symptoms be related to nonacid reflux? The short answer is.

0 1. PPIs won hands down over the H2 blocker. Again. et al. 2001. ranitidine 300 mg Lansoprazole 30 mg (n = 948) Omeprazole 20 mg (n = 1575) Pantoprazole 40 mg (n = 249) Rabeprazole 20 mg (n = 338) 0. showing that the greater the suppression of acid the better the healing rate of esophagitis. 3 .25 1.75 2. come back to the acid for just a minute. Clin Ther. It basically compared healing rates of erosive esophagitis with the 4 proton pump inhibitors shown in the left versus ranitidine the H2 receptor antagonist.0 Favors PPI PPIs were superior to ranitidine for healing of esophagitis at 8 weeks P < 0.75 Favors H2RA 1.Meta-analysis of PPIs Versus H2RAs for Erosive Esophagitis Healing Healing rate ratio (95% CI) vs.5 1. This is a very nice meta-analysis that you see summarized in front of you.05 for all PPIs vs. ranitidine 300 mg Caro JJ. no surprise to anybody in the room.23:998-1017. Now.

0 86. So.6 62. 2002. Am J Gastroenterol.01 (Cochran-Mantel-Haenszel test) 100 80 60 40 20 0 91.1 84. and D. 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.7 86. C.97:575-583. I was fortunate to the be the first author of this. 4 .6 79.Percentage Healing by Baseline Erosive Esophagitis Grade Lansoprazole 30 mg Percentage of patients healed Esomeprazole 40 mg P < 0.3 74. what is the largest multicenter study ever done in the treatment of reflux disease with PPIs. there is no question that we can heal this erosive disease. and we separated them into grades A. the Los Angeles classification for reflux disease. B.7 Grade A (n = 1878) Grade B (n = 2076) Grade C (n = 959) Grade D (n = 327) Castell D. over 5000 patients from the United States.3 91.

5 36.05) PPI response Placebo response NERD n = 705 Dean BB.7 (P < 0.2:656-664.0001) (P > 0.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. 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. So. if you look at the right-hand side of the slide. Basically. Clin Gastroenterol Hepatol. do you call them NERDs?—the results are even much worse. et al. what we call NERDs—do you guys do that. Only about a third of these patient became totally asymptomatic with their PPI therapy. 5 . Over in the nonerosive reflux group. What about symptom resolution? This again is a review paper by Dean and Ronnie Fass’ group out at the University of Arizona. but it is only 55% of the patients that are without any residual symptoms. EE The problem is shown here.5 7. do symptoms continue despite acid suppression? Absolutely. 2004. but notice there is an excellent symptom response.5 50 40 30 20 10 0 n = 1854 9. I think we have begun to recognize that over the last few years.

Barium esophagram 2. Combined impedance pH (MII-pH) monitoring 4.Audience Question • Which diagnostic test can detect nonacid reflux (reflux with pH ≥ 4)? 1. Audience question—which diagnostic test can detect nonacid reflux? And I’m going to define that as reflux with a pH of 4 or greater. 3. Barium esophagram pH-metry Combined impedance-pH (MII-pH) monitoring Endoscopy All right. 2. 4. pH-metry 3. it is time for you to step up to the plate here. Endoscopy 6 . I want you to vote: 1.

let’s talk a little bit more about this tool. Again. . obviously the message is coming across loud and clear. you have to have the right tool to do it with. If you really want to measure nonacid reflux.Audience Question Results • 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. this is a little bit of a mini-summary here. So. You have heard all of this already.

101:1956-1963. 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. Please understand. 8 . Am J Gastroenterol. Sifrim D. However. et al. Ambulatory combined impedance and pH. whereas a pH only indicates whether it is acid or nonacid. the combined technology is the key. et al. Gut. That is why I prefer the term nonacid reflux to cover any refluxate with a pH above 4. It detects reflux of all types at multiple levels in the esophagus. For 30 years we have used a pH of less than 4 as our threshold for acid reflux.53:1024-1031. Most of it is the food that the patient has ingested. With this technique. MII detects the presence of the reflux. your pH electrode now becomes a qualitative marker that identifies what type of reflux impedance is showing you. So.Ambulatory MII-pH Monitoring • Detects gastroesophageal reflux of all types at multiple levels of the esophagus • With this technique. 2006. 2004. the impedance detects the presence of a liquid reflux or of a gas reflux. strictly speaking chemically. if you simultaneously measure bile with a bilirubin detector in the esophagus that most of the nonacid reflux does not contain bile. weakly acidic applies correctly to the refluxate with a pH between 4 and 7.

Br J Surg. what we did. if I was referred a patient who was symptomatic on a PPI. Up until 5 years ago.93:1483-1487. 9 . this is what I would have done. 2006.Combined MII-pH Catheter pH catheter LES Adapted from Mainie I. in fact. et al. Let me show you the catheter we have been using.

Br J Surg. so I could measure whether there was ongoing reflux. et al. 2006. 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. 10 .Combined MII-pH Catheter pH catheter 5 cm Esophageal pH LES Gastric pH Adapted from Mainie I.93:1483-1487. We placed a pH catheter with dual electrodes. acid reflux if you will.

et al.Combined MII-pH Catheter pH catheter 5 cm Esophageal pH LES Gastric pH Adapted from Mainie I. Now. so that impedance is measured between each pair. we would modify that catheter here by placing a series of rings. as you saw earlier. 11 . 2006. Br J Surg. the electrical resistance is sampled.93:1483-1487.

and 17 cm above the lower sphincter.Combined MII-pH Catheter pH catheter Impedance 17 cm 15 cm 9 cm 7 cm 5 cm 3 cm 5 cm Esophageal pH LES Gastric pH Adapted from Mainie I. 15. This allows me now to measure the presence of fluid at 3. 2006. 12 . 5. Br J Surg. 9. et al. 7.93:1483-1487.

93:1483-1487. 2006.pH catheter Impedance 17 cm 15 cm 9 cm 7 cm 5 cm 3 cm 5 cm Esophageal pH LES Gastric pH Adapted from Mainie I. Br J Surg.Combined MII-pH Catheter MII. The data that I am going to show you subsequently were all collected using that catheter. et al. That is the MII-pH catheter. 13 .

We worked with these 2 young men. people with heartburn 3 times per week or more. So. Then we put the patients back on their PPI for a week. and we redid the experiment. Your pH probe does not tell you this is happening. PPI therapy does not stop postprandial reflux. 12 individuals. give them a big meal that induces reflux and test them with this new device.120:1599-1606. 14 . 2001. et al. You will notice down at the bottom the first author.02) (45%) (55%) n=7 (3%) On PPI Nonacid (P = 0. This is only a postprandial study right now. now 97% of them are nonacid. This was the study. This was the original seminal study that we did at the graduate hospital in Philadelphia. a young man by the name of Marcella Vela from Guatemala. “If I take a group of patients with regular GERD symptoms. His partner in crime here was a man from Romania by the name of Radu Tutuian. 55% were nonacid because the meal has buffered the gastric contents for the first hour particularly. As the slide says at the bottom. What happened? Well. There were 217 reflux episodes. also a very bright young investigator. Gastroenterology. it only changes the nature of the refluxate. what do I find?” That is what is shown on the left. If you do not know Marcella. We basically asked the question. Phil Katz and myself. So. You would not expect if would do otherwise. then it becomes more acidified for the second hour. here in the gray. we did not change the number of reflux episodes. I hope you get to know him. He is very bright. and I take them off their therapy. 2 hours postprandial. Most of them.03) PPI therapy does not stop postprandial reflux – it only changes the nature of the refluxate *2-hour postprandial Vela MF. but we got rid of the acid.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.

7. about 2 per hour. the same amount of postprandial reflux.3 2. On the left. are acid. as you would expect.7 Off PPI (n = 40) 5.7 2 1 0 1st hour 2nd hour postprandial postprandial Total 1st hour postprandial 2nd hour postprandial Blonski W. Gastroenterology. the results in 70 patients studied for 24 hours with impedance pH on PPI therapy. but after a meal. The differences are.132(4 suppl 2):A-288. the results numerically are exactly the same. about 2.3 episodes per hour. again. Now. Over here off PPI. et al. So. are nonacid. the second hour a little bit more. a young investigator from Poland who was working with us in the laboratory. the first hour. Abstract S1959.8 4.4 6 5 Nonacid Acid 6 5 4 3 Episodes per hour 4 3 2 1 0 Total 3. we have looked at the same thing just recently in 24-hour monitoring. a little bit more basal reflux. 15 . most of the reflux episodes. most of the reflux. These are his data presented at DDW earlier this year. it confirms very nicely what you would expect. the gray parts of the bar. This is a slide by Wojciech Blonski. A group of 40 patients studied off PPI.3 1. Average number of reflux episodes per hour in the total study was 1. 2007. almost 6 per hour and a little less in the second hour. the yellow portions of the bar. Over here on PPI therapy. the acidity.PPI Therapy Does Not Decrease Postprandial Reflux On PPI (n = 70) 5.

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. in another 200. We now have data. 2006. 16 . They have to be taking a standard PPI before breakfast and before dinner. so we have over 400 patients studied. “When is the last time you saw a patient with GERD that was not already taking a PPI?” In the adult world. Br J Surg.93:1483-1487. That is the buy-in. and somebody has already alluded to this. Now. by the way. when you put a catheter down somebody’s nose. 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. in order to get cooperation. So. we did a pretty good job. 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. You know. In fact.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. the answer is almost always “Never.” We do not see PPI-naive patients anymore. I often like to stop at this point with a group of gastroenterologists and ask the question. et al.

93:1483-1487. Br J Surg. 17 .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 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 Mainie I. et al. 2006. Only 14% of our patients failed to have symptoms during their 24-hour monitoring.

Br J Surg.93:1483-1487. 2006. were symptomatic. therefore. 18 . et al. 86%.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 Symptoms Symptoms during during 24-hour 24-hour MII-pH MII-pH monitoring monitoring n n= = 172 172 (86%) (86%) 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 Mainie I.

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 Symptoms Symptoms during during 24-hour 24-hour MII-pH MII-pH monitoring monitoring n n= = 172 172 (86%) (86%) No No symptoms symptoms during during 24-hour 24-hour MII-pH MII-pH monitoring monitoring n n= = 28 28 (14%) (14%) + SI Nonacid Nonacid reflux reflux n n= = 61 61 (35%) (35%) SI = symptom index Mainie I. et al. 19 . positive symptom index for reflux with their symptom with nonacid reflux about 35%. 2006. Br J Surg. What did we find in those 172 patients? Well.93:1483-1487.

they should not be having acid as a cause of their continuing symptoms. If you have somebody on a PPI twice per day appropriately dosed. In our experience. Br J Surg.93:1483-1487. you can almost take that to the bank. 2006.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 Symptoms Symptoms during during 24-hour 24-hour MII-pH MII-pH monitoring monitoring n n= = 172 172 (86%) (86%) + SI No No symptoms symptoms during during 24-hour 24-hour MII-pH MII-pH monitoring monitoring n n= = 28 28 (14%) (14%) + SI Nonacid Nonacid reflux reflux n n= = 61 61 (35%) (35%) SI = symptom index Acid Acid reflux reflux n n= = 13 13 (8%) (8%) Mainie I. 20 . et al. The least common finding is a positive symptom index for ongoing acid reflux.

21 . the most common finding was that the symptoms were not associated with reflux. ‘Darn. 57%.” but do not underestimate the clinical utility of that finding. we said. et al. 2006.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 Symptoms Symptoms during during 24-hour 24-hour MII-pH MII-pH monitoring monitoring n n= = 172 172 (86%) (86%) – SI Symptoms Symptoms not not associated associated with with reflux reflux n n= = 98 98 (57%) (57%) + SI No No symptoms symptoms during during 24-hour 24-hour MII-pH MII-pH monitoring monitoring n n= = 28 28 (14%) (14%) + SI Nonacid Nonacid reflux reflux n n= = 61 61 (35%) (35%) SI = symptom index Acid Acid reflux reflux n n= = 13 13 (8%) (8%) Mainie I.93:1483-1487. but pretty close. Br J Surg. that is kind of a negative result. that allows you to essentially eliminate reflux as a cause of the ongoing symptoms and to direct your approaches in another direction. As you have already figured out. When we first did this. It is not 100%.

101:1956-1963.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. they found 20% ongoing acid reflux. They commented that regurgitation and cough had the most frequent symptom association with nonacid reflux. but almost the same frequency of nonacid reflux with symptom probability. 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. similar results have been published at actually the same time as ours. 2006. Now. It is a French-Belgium consortium multicenter study. here are 60 patients on PPI. Am J Gastroenterol. 22 . 32%. but like our 200 patients. The 2 papers both came out last year by Frank Zerbib and colleagues from France. et al.

2. Lansoprazole 3.Audience Question • Which of the following medications decreases transient lower esophageal sphincter relaxations? 1. 4. Baclofen 23 . Metoclopramide 2. question again: which of the following medications decreases transient lower esophageal sphincter relaxations? 1. Metoclopramide Lansoprazole Imipramine Baclofen All right. Imipramine 4. 3.

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

Gut.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. Peghini PL. which is what you do when you give a PPI. I mentioned imipramine already as a way to decrease the patient’s sensation from the reflux episodes because you could take the approach that with the acid removed the damaging aspect is no longer there. I will show you one study with baclofen in just a minute. 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. I wish there was. We use Gaviscon with its alginic acid component as a PRN therapy for these. Practical Gastroenterol. wouldn’t it be nice if we had one—should be considered. then I should consider that.42:807-813. obviously immediately comes to the fore. Medically. 2006. There is minimal evidence from controlled studies on any of these. domperidone – To decrease visceral sensation: imipramine – To decrease reflux: alginic acid PRN • Endoscopic • Surgical – Fundoplication • Agrawal A.30:68-72. that actually can be effective in some of these patients. et al. 25 . 1998. Is there an endoscopic approach? Again. What about raising the resting LES pressure? Reach back now for an older drug. bethanechol. Surgery. we talked about baclofen because it will decrease transient LES relaxations. If I can get rid of the symptoms with a drug like imipramine. that is a fundoplication. Symptomatic nonacid reflux: I want you to begin to think about reflux reduction therapies rather than acid reduction therapies. as has already been mentioned. et al. What about trying to improve gastric emptying if the patients have delayed gastric emptying? Here again a more standard promotility drug—again.

and acid re-reflux because of the transient LES relaxation effect. acid reflux.05 Vela MF. et al. 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. 2003. Marcella Vela. Aliment Pharmacol Ther. Acid Nonacid Re-reflux Now. before we left Philadelphia at the beginning of this decade. Again.17:243-251. a couple of quick slides on baclofen. nonacid reflux.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. 26 . baclofen (shown in yellow) significantly decreased total reflux.

et al. anxiety Ciccaglione AF. Gut. 2003. 27 . 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. placebo – Baclofen decreased GER episodes and percentage of time pH < 4 (acute and chronic) – Baclofen decreased acid GER and symptoms • Side effects: dizziness. They did both a 24-hour pharmacologic study. and the side effects were CNS in type—dizziness. if you will.52:464-470. it is a small one that is in the literature.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. anxiety—and the things that you know about with this drug. Baclofen decreased acid reflux and symptoms. both in the acute and chronic study. They were looking at pH here by the way. The one controlled study. came from Italy with 28 patients and 15 controls.

Castell) Thank you very much for your comments everybody. It comes back in a lot of people and varying time. Some relapses certainly do occur. there was a child I looked after without neurological deficit. (Dr. but also with the right surgeon and the right selection of patients. Castell) OK. I can give an example. (Dr. In your experience. too. (Dr. had a 3-4 cm hiatal hernia. (Dr. Castell) Where are you? I cannot see you. (Audience) What about reflux nonresponsive to medical therapy? (Dr. we have a volunteer right here. very careful circumstances you have to tell them that the control is not permanent. if you will. Castell) Pathologic reflux that has not responded to therapies. responded to 90 mg of lansoprazole. can be a very good procedure. under what conditions should surgery be recommended for patients? All right. Yes. One more comment. Because the child responded. This is an interaction question. (Audience) This is Dr. Gold) Don. we all as a group who are sitting here know the outcome is not very good. in children with neurological deficits and chronic respiratory problems. It does not correct the pathophysiology. Don. So. Gold) I am all the way in the back. I think we heard some of the things that we all understand about surgery. so surgery has not been very successful in our group of patients that I have followed over the last 30 years. It does have the tendency for extra effects. (Dr. had grade C LA classification of esophagitis. (Audience) I am from Chicago. Castell) OK. Chandra from Pittsburgh. I think I would support and not support surgery with fundoplication. Gold) We have one in the back. Castell) All right. then I sent the child to surgery. this is not a correction of the pathophysiological process. it induces a vagal damage in many patients and increases the gastric emptying problems. Also. so under very. (Dr. I think. (Dr. Furuta) We have a volunteer back here. it is a placebo procedure. under what conditions should surgery be recommended for GERD patients? That is a fundoplication. (Dr. and the child had a very good outcome because the child had a great pediatric surgeon. It does have its limitations. (Audience) Pathologic reflux. 28 . (Dr.Audience Interaction • In your experience. The response to surgery is poor and unpredictable.

9 typical symptoms) LNF = laparoscopic Nissen fundoplication Mainie I. Let me show you the piece of outcomes data that we obtained at the Medical University of South Carolina. Again. had atypical GERD symptoms. these are from those first 200 patients that we monitored that were on a PPI twice per day. et al. Here were the diagnostic findings. the other 9 had typical GERD symptoms. interestingly. 29 . 10 that is.A Surgical Approach to Patients Who Fail Acid Suppression Treatment 19 patients undergoing LNF (10 atypical symptoms. that is supraesophageal symptoms. Nineteen patients that had a laparoscopic Nissen fundoplication. 2006. Br J Surg.93:1483-1487. half of them.

Positive symptom index for nonacid reflux was 14 patients.A Surgical Approach to Patients Who Fail Acid Suppression Treatment 19 patients undergoing LNF (10 atypical symptoms.93:1483-1487. 2006. I will show you the response in a minute. 30 . Interestingly. half of them had chronic cough. Br J Surg. 9 typical symptoms) Patients with positive symptom index (nonacid) (n = 14) LNF = laparoscopic Nissen fundoplication Mainie I. et al.

2006. Br J Surg. et al. Four patients had a positive symptom index for acid. 9 typical symptoms) Patients with positive symptom index (nonacid) (n = 14) Patients with positive symptom index (acid) (n = 4) LNF = laparoscopic Nissen fundoplication Mainie I.A Surgical Approach to Patients Who Fail Acid Suppression Treatment 19 patients undergoing LNF (10 atypical symptoms.93:1483-1487. 31 .

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) LNF = laparoscopic Nissen fundoplication Mainie I. by the way.A Surgical Approach to Patients Who Fail Acid Suppression Treatment 19 patients undergoing LNF (10 atypical symptoms. et al. if you will. that was a failure and is one of our controls. did not have reflux demonstrated with symptoms. Br J Surg.93:1483-1487. but the surgeon operated anyway. 2006. One patient. 32 .

93:1483-1487. 2006. Here are the results in the 18 patients that actually had reflux demonstrated by testing. were still off PPI with symptom response at the end of the 14 months’ follow-up. 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) 94% of patients with positive symptom index were asymptomatic or markedly improved after mean follow-up of 14 months (range 7-25 months) LNF = laparoscopic Nissen fundoplication Mainie I. 17. which was the period of time that we followed them. Br J Surg.A Surgical Approach to Patients Who Fail Acid Suppression Treatment 19 patients undergoing LNF (10 atypical symptoms. 33 . et al. that is 94%.

Br J Surg. 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) 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. 2006.A Surgical Approach to Patients Who Fail Acid Suppression Treatment 19 patients undergoing LNF (10 atypical symptoms. So.93:1483-1487. 34 . 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.

which we see much less of today. 35 . were present. esophageal acid exposure and things like the DeMeester score were important because we did not have a good way to control the acid. Esophagitis and strictures. Mucosal injury was rampant. the world changed with omeprazole. Prior to 1989.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. Symptom relief was a secondary end point. that is the pre-PPI era.

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

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 37 .

Changing GERD Paradigm • 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. 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. where the impedance technique allows us to measure all of the reflux and understand the disease and the symptoms better. 38 .

39 .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.

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and if you took nothing else away from my presentation. We have identified it as a finding in reflux disease. and I think something that all of you have been excited about at some point. He is the associate professor at the University of Colorado and Health Sciences Center. and one of the early lessons that he taught me was always have a SOCO (Single Overriding Communicable Observation). it is late. 1 . Allergy. or Something Else? Glenn T. who still says that he is a Red Sox fan. and it is the challenge for all of the fellows and the trainees in the room. Ben and I have known each other for a long time. and I know you guys have been sitting in meetings all day. although now lives in Denver. We are going to have Glenn Furuta. MD Associate Professor University of Colorado at Denver and Health Sciences Center Denver. I think in 2007 the real message is that eosinophilic inflammation is a multifaceted histological finding that has a diverse set of etiologies. So. Gold) All right and now moving on to the last. but the upcoming decades are really going to lend us to more investigations of understanding it is a hallmark of other disease. We have started to understand more about eosinophilic disease.What Do Eosinophils in the Esophagus Really Mean: Acid. CO (Dr. He is going to discuss: “What Do Eosinophils in the Esophagus Really Mean. Allergy or Something Else?” (Dr. We had the opportunity last year preceding the NASPGHAN meeting to hear a whole day. Furuta) Thank you Ben. Furuta. Acid. but definitely not least.

and reflux-like symptoms. Eosinophilic esophagitis 3. food impaction and reflux-like symptoms. GERD 2. food impaction. The patient’s pH monitoring records normal pH levels. Based on this information. we are going to start with an audience questions about eosinophilic esophagitis and eosinophilic inflammation. Based on this information. what is the diagnosis for this patient? 1. The patient’s endoscopy reveals whitish plaques and longitudinal shearing. A patient presents with dysphagia. The patient’s pH monitoring records normal pH levels. what is the diagnosis? 1. Eosinophilic esophagitis 3. Not enough information So. Not enough information 2 .Audience Question • A patient presents with dysphagia. GERD 2. The patient’s endoscopy reveals whitish plaques and longitudinal shearing.

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

Differentiating GERD From Eosinophilic Esophagitis GERD Pathogenesis Transient relaxation of lower esophageal sphincter Heartburn. 4 . The histology can appear the same in both disease. but they are shown here. In fact. 2004. 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. 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. Symptoms vomiting/regurgitation Exudate. and there are no real symptoms that truly identify or separate these diseases. that helped us to try to differentiate some of the features of this disease. reflux-like symptoms Longitudinal shearing. basal zone hyperplasia. allergy.2:523-530. and gastroenterology. epigastric pain. but because the finding is somewhat unusual. indeed. In data that we have presented last year. et al. erosions. rings. as well as EE. friability. suggests that it is a function of transient relaxations of the LES. we will show a little bit later in the presentation. Clin Gastroenterol Hepatol. the pathogenesis of this disease. So. both adult and pediatric. how do we differentiate eosinophilic esophagitis from reflux disease. papillae elongation pH monitoring Acid reflux Treatment PPI Long-term Strictures (distal). clearly you can have increased numbers of eosinophils in both reflux. Endoscopically. whitish plaques Histology Eosinophils. as you have heard for reflux. dietary elimination Strictures (proximal) *No pathognomonic findings Arora AS. longitudinal shearing is probably one of the few features that is fairly specific. but more importantly identify diagnostic criteria. pH monitoring is suggestive if there is a normal pH probe in EE. but again there is not enough data yet to truly make that statement. The symptoms can cross over. We think that one of the other separating features might be the fact that there are proximal strictures in EE and not in GERD. food impaction. furrows. Endoscopy ulceration Eosinophilic Esophagitis* Possibly allergic Dysphagia. The treatments obviously are quite different and well known to you. there have not been studies yet to identify it as the only finding that would separate the 2 diseases. cancer complications Normal Steroids. Eosinophilic esophagitis. may have an allergic etiology.

Endoscopy ulceration Eosinophilic Esophagitis* Possibly allergic Dysphagia. epigastric pain. Clin Gastroenterol Hepatol. erosions. rings. papillae elongation pH monitoring Acid reflux Treatment PPI Long-term Strictures (distal).2:523-530. cancer complications Normal Steroids. furrows. one needs to exclude GERD first. Symptoms vomiting/regurgitation Exudate. whitish plaques Histology Eosinophils. friability. 2004. reflux-like symptoms Longitudinal shearing. basal zone hyperplasia. et al. 5 . dietary elimination Strictures (proximal) Exclude GERD before making diagnosis of eosinophilic esophagitis *No pathognomonic findings Arora AS. I think before making the diagnosis of eosinophilic esophagitis.Differentiating GERD From Eosinophilic Esophagitis GERD Pathogenesis Transient relaxation of lower esophageal sphincter Heartburn. food impaction.

Transient or fixed corrugated rings 4. 2. Longitudinal furrows White nodule. Longitudinal furrows 2. 5. 2 and 3 5. 4. None of the above 6 . White nodule or plaque-like exudates 3.or plaque-like exudates Transient or fixed corrugated rings 2 and 3 None of the above The second question—endoscopic findings that are pathognomonic for eosinophilic esophagitis include which of the following? 1.Audience Question • Endoscopic findings that are pathognomonic for eosinophilic esophagitis include which of the following? 1. 3.

There have not been any studies yet to truly identify any of these as pathognomonic for eosinophilic esophagitis. 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.or plaque-like exudates Transient or fixed corrugated rings 2 and 3 None of the above 16% 2% 5% 30% 47% OK. and whether that is swelling of the squamous epithelium. all of these are relatively nonspecific.Audience Question Results • Endoscopic findings that are pathognomonic for eosinophilic esophagitis include which of the following? Longitudinal furrows White nodule. . exudation of eosinophils through the epithelium. or fixed or transient motility disturbances.

2Image courtesy of G. MD. 8 .356:e20. Triadafilopoulos. All rights reserved. et al. Massachusetts Medical Society. we wanted to talk a little bit about the eosinophils themselves and their life cycle and how eosinophils may. 2007. So. in fact. Copyright© 2007. N Engl J Med.Eosinophilic Esophagitis Compared to Erosive Esophagitis Eosinophilic esophagitis1 Erosive esophagitis2 1Reproduced with permission from Hawari R. contribute to esophageal dysfunction.

eosinophils primarily reside in organs with a mucosal surface. the gut.24:173-182. and the genitourinary tract. et al. so. 9 .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. In that light. any organ that resides exposed to the environment has eosinophils present. so the eyes. They are born from the bone marrow progenitor cells and mature into a fully granulated state before they migrate into the vascular spaces. 2006. Aliment Pharmacol Ther.

Aliment Pharmacol Ther. et al. IL-5 is the most specific for eosinophils.Eosinophil Life Cycle (cont. Importantly. 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. in fact. interleukin-3 and GM-CSF also participate in that maturation. but.24:173-182. IL-3.) • Interleukin (IL)-5. 10 . one of the cytokines that is critical in the development of eosinophils is interleukin-5. 2006.

they migrate to the vascular space. under the direction of specific adhesion molecules that we will discuss in a few minutes. and then the target organ tissue. migrate through the endothelial space and into the mucosal surfaces. et al. In those mucosal surfaces. they encounter other cytokines and other activating factors that may allow them to participate in both host health and disease. That is shown here in this diagram.Eosinophil Life Cycle (cont. Then.) Maturation GATA-1 PU. They are born here under the direction of specific transcription factors. 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. 11 . You can see the cytokines that are involved in their maturation. where they reside briefly.24:147-174. 2006.1 c/EBP IL-3 GM-CSF IL-5 IL-5 αmβ2 αLβ2 ICAM-1 Bone Marrow Migration Blood α4β1 α4 β7 VCAM-1 MadCAM-1 Eotaxin-1 GI Tract Adapted from Rothenberg ME. Annu Rev Immunol. the vascular space. One can see the bone marrow. Under certain beckoning calls.

Gold) Volunteers? We have an answer for your question.” (Dr. We will show some evidence that may support that in one sense. the original description was by Harland Winter. I am glad you brought it up. but I think what we have learned now and if we looked at the history of eosinophilic inflammation of the esophagus. or exposure to allergens? So our audience interaction question: Is esophageal eosinophilia induced by exposure to acid or exposure to allergens? (Dr. Furuta) Acid disease. Furuta) So. (Dr. if the number is 10 per high-power field or 20 or more than 20.Audience Interaction • Is esophageal eosinophilia induced by exposure to acid. the whole diagnosis is dependent on the individual lab as for eosinophilic esophagitis. Dr. We will address this in just a few minutes. 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. Furuta. who noted that there were greater than 1 eosinophils present in the esophagus of children affected with reflux disease. you are saying the number of eosinophils dictates which. (Audience) That is great. (Audience) The answer is “Yes. they have larger numbers. So. Any other answers? 12 . It was only characterized in that sense of greater than 1. So. Gold) There is a fence-sitter for you. (Audience) It depends upon what the lab tech says the baseline is for eosinophilic esophagitis. Now that we have seen another clinical phenotype of patients who have symptoms that are nonresponsive to acid blockade. (Dr. I think it is an important discussion to have. also.

13 . and what is some of the basic evidence to support that observation.Acid-Inducing Eosinophilic Esophageal Inflammation So. we wanted to touch on this evidence that may suggest that. indeed. eosinophils can arrive in the esophagus.

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

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. esophageal blood flow can be increased by acid injury that could enhance the delivery of eosinophils. resulting in infiltration of eosinophils – Acid increases: • Esophageal blood flow. in observation.102:1301-1306. enhancing delivery of eosinophils GERD and eosinophilic esophagitis coexist. 15 . there has been very little in the sense of basic evidence to support these findings yet. in fact. but are unrelated Spechler SJ. Am J Gastroenterol. et al. Now.GERD and Esophageal Eosinophilia (cont. Additionally. GERD and eosinophilic inflammation may coexist. So. again.) • GERD causes esophageal injury. but. but may be unrelated. 2007. but not anything that has been yet supported by basic or translational evidence.

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

Spechler SJ, et al. Am J Gastroenterol. 2007;102:1301-1306.

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

Spechler SJ, et al. Am J Gastroenterol. 2007;102:1301-1306.

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

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 Hydrochloric Acid (HCl) in Mucosa Interleukin (IL)-1β Platelet-Activating Factor (PAF) PAF released in esophageal circular muscle causes the sequential production of IL-6. 2006. 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. H2O2. in turn. induces circular muscle to produce PAF (Data expressed as mean ± SEM) Cheng L. 19 .319:117-126. and IL-1β that. et al. In fact. J Pharmacol Exper Ther.

20 .319:117-126. in turn. H2O2. induces circular muscle to produce PAF (Data expressed as mean ± SEM) HCl produces PAFs. PAFs attract and activate eosinophils. 2006. So. Release of PAFs by the esophageal mucosa initiates sequential formation of inflammatory mediators. hydrochloric acid. Cheng L. and IL-1β that. indeed. et al. may participate in this inflammatory response.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 Hydrochloric Acid (HCl) in Mucosa Interleukin (IL)-1β Platelet-Activating Factor (PAF) PAF released in esophageal circular muscle causes the sequential production of IL-6. J Pharmacol Exper Ther.

is there any clinical evidence to support the fact that acid.Eosinophils in the Esophageal Epithelium With Acid Suppression Histologic Assessment of Esophageal Squamous Epithelium of 3 Patients. et al. 2006. 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. This is the pretreatment with proton pump inhibitor eosinophil counts. Well. 21 . You can see they are 37 and 6.101:1666-1670.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. 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. Pre. Am J Gastroenterol. indeed. this patient had a histological remission. Following 2 months of proton pump inhibition.

Eosinophils in the Esophageal Epithelium With Acid Suppression Histologic Assessment of Esophageal Squamous Epithelium of 3 Patients. 22 . The same findings were seen in the second patient who had 20 eosinophils. et al. 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 Patient 2 (25 yrs)† Pre 5 21 20 Post 3 3 0 * Treated with omeprazole 10 mg twice daily † Treated with omeprazole 20 mg twice daily ‡ Treated with omeprazole 20 mg daily Ngo P.101:1666-1670. 2006. Am J Gastroenterol.

and the same in a third patient who had up to 50 eosinophils per high-power field. et al. 2006. Am J Gastroenterol. 23 .Eosinophils in the Esophageal Epithelium With Acid Suppression Histologic Assessment of Esophageal Squamous Epithelium of 3 Patients.101:1666-1670. 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 Patient 2 (25 yrs)† Patient 3 (9 yrs)‡ Pre 5 21 20 Post 3 3 0 Pre 52 59 24 Post 0 0 0 * Treated with omeprazole 10 mg twice daily † Treated with omeprazole 20 mg twice daily ‡ Treated with omeprazole 20 mg daily Ngo P.

) Histologic Assessment of Esophageal Squamous Epithelium of 3 Patients. that we are looking at a different type of phenotype now that will be described over the next several decades. superficial layering of eosinophils. Am J Gastroenterol.Eosinophils in the Esophageal Epithelium With Acid Suppression (cont. et al. these were the findings in 3 children.101:1666-1670. and vomiting • Endoscopic features include white exudates and linear furrows.and Post-PPI Treatment 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. including eosinophil aggregates. 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. Importantly. 24 . suggesting allergy-induced esophagitis * Treated with omeprazole 10 mg twice daily † Treated with omeprazole 20 mg twice daily ‡ Treated with omeprazole 20 mg daily Ngo P. and basal zone hyperplasia as shown in each one of the patients had deep diminution or were lost following the proton pump inhibition.” I think again he emphasizes the fact that eosinophilic inflammation is not just due to 1 disease. Pre. 2006. So. the associative findings that are typically associated with eosinophilic esophagitis.

25 . much of the data and much of the support from this comes from clinical trials in the sense of treatment.Eosinophils in Allergy Injury: Evidence for Allergy-Inducing Esophageal Eosinophilia So. may be related to an allergic injury? Well. in fact. what is the evidence that eosinophils.

26 . et al. Chris Liacouras has the largest group of patients that he has followed now for over 10 years. Clin Gastroenterol Hepatol. He reported this 2 years ago and has experience with 381 patients.1 ± 3.Eosinophilic Esophagitis in Children: Pharmacologic Versus Dietary Therapy 381 pediatric patients over 10-year period (66% male.3:1198-1206.1 years) Liacouras CA. 2005. children. who had eosinophilic esophagitis. mean age 9.

The reasons for this could be certainly multiple in the sense of lack of adherence of the medication to the esophageal mucosa. that there is an allergic etiology.6 Before treatment 4 weeks into treatment 6 months off treatment 11.7 23. again the same finding. this suggests. You can see there is a marked diminution of eosinophils with topical steroids. 2005. when patients were to go off of these type of steroid preparations. Clin Gastroenterol Hepatol.5 28. 27 .3 25. So. But. 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. Cromolyn. in the sense of Gastrocrom. We still do not know exactly the role of mast cells in these diseases.Eosinophilic Esophagitis in Children: Pharmacologic Versus Dietary Therapy 381 pediatric patients over 10-year period (66% male. et al. in the sense of steroids.4 27.1 ± 3.9 33. was not effective in this.3:1198-1206. suggesting the necessity for a persistent immunomodulatory approach.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 0.5 28. because of the pharmacological approach.7 27. including systemic steroids.2 (n = 14) Liacouras CA. mean age 9. there is a significant increase in the eosinophils.

3:1198-1206. We know that food elimination diets. 28 .Eosinophilic Esophagitis in Children: Pharmacologic Versus Dietary Therapy (cont. 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. et al. Clin Gastroenterol Hepatol. 2005. can induce a remission in most patients. as well as the use of amino acid–based formula.) • Food elimination diet (exclusion of certain foods based on skin prick or skin patch allergy test) • Complete dietary elimination using only an amino acid–based formula (if allergy testing did not identify a specific food allergy) Liacouras CA.

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. et al.Eosinophilic Esophagitis in Children: 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 acid–based formula (if allergy testing did not identify a specific food allergy) 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. here are the prediet numbers of eosinophils.1 54 21 5. the symptoms.01 < 0.3 134 30 Food Elimination Diet (n = 75) 47. and the symptom score.3 ± 2. So.5 ± 12.7 2 1 < 0.01 Postdiet 1.6 3 1 P value < 0. 2005.01 Amino Acid–Based Formula (n = 160) Liacouras CA. 29 . as well as dysphagia prediet and postdiet with the use of a food elimination diet.001 < 0. Clin Gastroenterol Hepatol.001 < 0. as well as an amino acid–based formula.7 ± 10.01 < 0.1 ± 0.3:1198-1206.

suggesting that if you were able to remove the offending allergen that you could get reduction in the number of eosinophils.3 134 30 Food Elimination Diet (n = 75) 47.01 Amino Acid–Based Formula (n = 160) CONCLUSION: Removal of dietary antigens significantly improved clinical symptoms and esophageal histology in 98% of patients Liacouras CA.1 54 21 5. 30 .001 < 0.01 < 0.Eosinophilic Esophagitis in Children: Pharmacologic Versus Dietary Therapy (cont.7 ± 10.001 < 0.5 ± 12.) • Food elimination diet (exclusion of certain foods based on skin prick or skin patch allergy test) • Complete dietary elimination using only an amino acid–based formula (if allergy testing did not identify a specific food allergy) 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. 2005.01 Postdiet 1.3:1198-1206.6 3 1 P value < 0. et al.7 2 1 < 0.1 ± 0.3 ± 2.01 < 0. Clin Gastroenterol Hepatol.

peanut. and seafood • Elemental Diet (ELED) – crystalline amino acid–based diet Kagalwalla AF. soy. and he said that really the difficulty in identifying the exact allergen is very significant. 2006.4:1097-1102.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. the 6 most common foods that can cause an allergic response. Amir Kagalwalla took a different approach to this treatment. So. Clin Gastroenterol Hepatol. wheat. egg. He performed a retrospective observational study comparing patients who had 6 foods eliminated to those who were treated with an elemental diet. 31 . out of the diet and see what happens to the patients. So. et al. let’s just take all of the most common food allergens.

32 .2 N (%) 3 (9%) Peak Eosinophil* 15. so that these are greater than 10 eosinophils. peanut. went into both clinical.1 N (%) 6 (17%) Peak Eosinophil* 58. This is the side of the slide. The bottom line from this was that approximately 75% of patients who had 6 foods eliminated from their diet.0 Postbiopsy exam (peak eosinophil count) 13.0 ± 29.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. There is the prebiopsy count and the postbiopsy count.2 ± 44. wheat. soy. and seafood • Elemental Diet (ELED) – crystalline amino acid–based diet Significant improvement Partial improvement Treatment Failure (11-20 eosinophils per HPF) (> 20 eosinophils per HPF) (≤ 10 eosinophils per HPF) Type of diet SFED N N (%) 26 (74%) Peak Eosinophil* 3.0001 Kagalwalla AF. Clin Gastroenterol Hepatol. Importantly. So.8 P value 35 < 0. 2006. the type of diet is shown on the far left-hand slide. and then treatment failures of greater than 20 eosinophils per high-power field. The results are shown here. you can see that this is divided into 3 different sections. partial improvement with 11 to 20.1 ± 3. indeed. the 6-food elimination diet. as well as histological remission. et al. egg.4:1097-1102.2 Prebiopsy exam (peak eosinophil count) 80.7 ± 2.6 ± 23.

2 Prebiopsy exam (peak eosinophil count) 80.5 < 0.2 N (%) 3 (9%) 2 (8%) Peak Eosinophil* 15. The same kinds of findings were shown. supporting a role for allergens. as well as clinical remission.0001 ELED 25 1. except there were approximately 88% of patients who ended up going into histological. suggesting that the removal of specific allergens that could be associated with eosinophilic inflammation induces a remission.6 ± 6.8 P value 35 < 0.2 ± 44. Clin Gastroenterol Hepatol.0 ± 29.001 * Peak eosinophil count: mean for the group ± SD of each group Kagalwalla AF.0 ± 2. and seafood • Elemental Diet (ELED) – crystalline amino acid–based diet Significant improvement (11-20 eosinophils per HPF) (> 20 eosinophils per HPF) Partial improvement Treatment Failure (≤ 10 eosinophils per HPF) Type of diet SFED N N (%) 26 (74%) 22 (88%) Peak Eosinophil* 3. et al. This was compared to the elemental diet shown here.8 N/A 58.6 ± 2.4:1097-1102. 33 . egg. 2006. So.7 ± 2.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.9 3.6 ± 23. wheat. again.1 ± 3.8 ± 31.0 Postbiopsy exam (peak eosinophil count) 13. peanut. soy.1 15.1 N (%) 6 (17%) 1 (4%) Peak Eosinophil* 58.

A diagnosis of EE should be reserved for patients who have characteristic endoscopic and histological features who are not responsive to proton pump inhibition.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. Thank you. contributory to many of the patients who have EE. the interaction between GERD and eosinophilic esophagitis in pediatric patients is going to be complex. indeed. to summarize. 34 . I think it is complex now in our daily care. and future studies will be needed to determine more about the etiologies leading to esophageal eosinophilia. but I think we are going to see even more complexities in the future. Food allergies are.

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