Susan R. Orenstein

The spectrum of pediatric eosinophilic esophagitis beyond infancy: a clinical series of 30 children

OBJECTIVES:Eosinophilic esophagitis, previously confused with esophageal inflammation due to gastroesophageal reflux, has recently begun to be distinguished from it. We undertook this analysis of our large series of children with the condition to clarify its spectrum: its presenting symptoms; its relation to allergy, respiratory disease, and reflux; its endoscopic and histological findings; and its diagnosis and therapy.METHODS:We analyzed the details of our clinical series of 30 children with eosinophilic esophagitis, defining it as ≥5 eosinophils per high power field in the distal esophageal epithelium. Retrospective chart review was supplemented by prospective, blinded, duplicate quantitative evaluation of histology specimens, and by telephone contact with some families to clarify subsequent course. Presentation and analysis of the series as a whole is preceded by a case illustrating a typical presentation with dysphagia and recurrent esophageal food impactions.RESULTS:Presenting symptoms encompass vomiting, pain, and dysphagia (some with impactions or strictures). Allergy, particularly food allergy, is an associated finding in most patients, and many have concomitant asthma or other chronic respiratory disease. A subtle granularity with furrows or rings is newly identified as the endoscopic herald of histological eosinophilic esophagitis. Histological characteristics include peripapillary or juxtaluminal eosinophil clustering in certain cases. Association with eosinophilic gastroenteritis occurs, but is not common. Differentiation from gastroesophageal reflux disease is approached by analyzing eosinophil density and response to therapeutic trials. Therapy encompasses dietary elimination and anti-inflammatory pharmacotherapy.CONCLUSION:Awareness of the spectrum of eosinophilic esophagitis should promote optimal diagnosis and treatment of this elusive entity, both in children and in adults.

A Global, Evidence-Based Consensus on the Definition of Gastroesophageal Reflux Disease in the Pediatric Population

OBJECTIVES:To develop an international consensus on the definition of gastroesophageal reflux disease (GERD) in the pediatric population.METHODS:Using the Delphi process, a set of statements was developed and voted on by an international panel of eight pediatric gastroenterologists. Statements were based on systematic literature searches using Medline, EMBASE, and CINAHL. Voting was conducted using a six-point scale, with consensus defined, a priori, as agreed by 75% of the group. The strength of each statement was assessed using the GRADE system.RESULTS:There were four rounds of voting. In the final vote, consensus was reached on 98% of the 59 statements. In this vote, 95% of the statements were accepted by seven of eight voters. Consensus items of particular note were: (i) GERD is present when reflux of gastric contents causes troublesome symptoms and/or complications, but this definition is complicated by unreliable reporting of symptoms in children under the age of ∼8 years; (ii) histology has limited use in establishing or excluding a diagnosis of GERD; its primary role is to exclude other conditions; (iii) Barretts esophagus should be defined as esophageal metaplasia that is intestinal metaplasia positive or negative; and (iv) extraesophageal conditions may be associated with GERD, but for most of these conditions causality remains to be established.CONCLUSIONS:The consensus statements that comprise the Definition of GERD in the Pediatric Population were developed through a rigorous process. These statements are intended to be used for the development of future clinical practice guidelines and as a basis for clinical trials.

Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease.

OBJECTIVE To assess the efficacy and safety of lansoprazole in treating infants with symptoms attributed to gastroesophageal reflux disease (GERD) that have persisted despite a >or= 1-week course of nonpharmacologic management. STUDY DESIGN This multicenter, double-blind, parallel-group study randomized infants with persisting symptoms attributed to GERD to treatment with lansoprazole or placebo for 4 weeks. Symptoms were tracked through daily diaries and weekly visits. Efficacy was defined primarily by a >or= 50% reduction in measures of feeding-related crying and secondarily by changes in other symptoms and global assessments. Safety was assessed based on the occurrence of adverse events (AEs) and clinical/laboratory data. RESULTS Of the 216 infants screened, 162 met the inclusion/exclusion criteria and were randomized. Of those, 44/81 infants (54%) in each group were responders--identical for lansoprazole and placebo. No significant lansoprazole-placebo differences were detected in any secondary measures or analyses of efficacy. During double-blind treatment, 62% of lansoprazole-treated subjects experienced 1 or more treatment-emergent AEs, versus 46% of placebo recipients (P= .058). Serious AEs (SAEs), particularly lower respiratory tract infections, occurred in 12 infants, significantly more frequently in the lansoprazole group compared with the placebo group (10 vs 2; P= .032). CONCLUSIONS This study detected no difference in efficacy between lansoprazole and placebo for symptoms attributed to GERD in infants age 1 to 12 months. SAEs, particularly lower respiratory tract infections, occurred more frequently with lansoprazole than with placebo.

Reflux Symptoms in 100 Normal Infants: Diagnostic Validity of the Infant Gastroesophageal Reflux Questionnaire

To identify the prevalence of reflux symptoms in normal infants, to characterize the diagnostic validity of a previously described 138-item Infant Gastroesophageal Reflux Questionnaire (I-GERQ) for separating normal infants from those with gastroesophageal reflux disease (GERD), and to identify potentially provocative caretaking practices, we administered the questionnaire to 100 infants attending a well-baby clinic (normals) and to 35 infants referred to the Gastroenterology Division for evaluation for GERD and testing positive on esophageal pH probe or biopsy (GERD infants). Differences were analyzed by Chi-square, and odds ratios were defined. The diagnostic validity of a 25-point I-GERQ GERD score based on 11 items on the questionnaire was evaluated by calculating its sensitivity, specificity, and positive and negative predictive values. We found that normal infants had a high prevalence of reflux symptoms, such as daily regurgitation (40%), respiratory symptoms, crying more than an hour a day (17%), arching (10%), or daily hiccups (36%) but that many symptoms were significantly more prevalent in the GERD than in the normal infants (Chi-square P<.05), and odds ratios were above 3 for nearly 20 items. The positive and negative predictive values for the 25-point I-GERQ score were 1.00 and .94-.98, respectively. Environmental smoke exposure did not quite reach significance as a provocative factor for GERD. Although normal infants have a high prevalence of symptoms suggesting GERD, a simple questionnaire-based score is a valid diagnostic test with high positive and negative predictive values.

Thickening of infant feedings for therapy of gastroesophageal reflux

To assess the effect of thickening of feedings on gastroesophageal reflux and gastric emptying, 20 infants were examined with technetium scintigraphy and detailed behavioral observation after each of a pair of feedings, one with radiolabeled infant formula alone and the other with radiolabeled formula thickened with dry rice cereal. The thickened and unthickened meals were followed by similar amounts of scintigraphically demonstrated gastroesophageal reflux. However, the number of episodes of emesis (1.2 +/- 0.7 vs 3.9 +/- 0.9 per 90 minutes postprandial), the percent of gastric emptying at 30 minutes (17.8% +/- 2.7% vs 22.4% +/- 2.4%), the time spent crying (11.7 +/- 3.1 minutes vs 17.6 +/- 3.8 minutes per 90 minutes), and the total time spent awake (45.2 +/- 5.9 minutes vs 53.1 +/- 4.9 minutes per 90 minutes) were significantly less after the thickened feedings. Because thickening of infant feedings increases the caloric density, decreases emesis, decreases crying time, and increases sleep time in the postprandial period, it is likely to be beneficial in the treatment of infants with gastroesophageal reflux associated with failure to thrive.

Eosinophilic esophagitis: strictures, impactions, dysphagia.

Eosinophilic esophagitis, long known to be a feature of acid reflux, has recently been described in patients with food allergies and macroscopically furrowed esophagus. The pathophysiology and optimal management of patients with eosinophilic esophagitis is unclear. We describe our clinical experience related to eosinophilic esophagitis and obstructive symptoms in children and propose etiopathogenesis and management guidelines. Twelve children with obstructive esophageal symptoms (11 male), median age 5 years, and identified to have eosinophilic esophagitis with >5 eosinophils per high-power field (eos/hpf) are reported. Of these, four had strictures, six had impactions, and two had only dysphagia. A diagnostic evaluation included esophagogastroduodenoscopy with biopsies in all and upper gastrointestinal series, IgE, radioallergosorbent tests, and skin tests for food allergies in some cases. Esophageal histology specimens were independently analyzed for eosinophil density by two authors. Four of five children with >20 eos/hpf responded to elimination diets/steroids. The fifth child responded to a fundoplication. Seven children had 5–20 eos/hpf and three of them with no known food allergies responded to antireflux therapy alone. Three others in this group with positive food allergies responded to treatment with elimination diets and/or steroids. The seventh patient in this group was lost to follow-up. In conclusion, on the basis of response to therapy, eosinophilic esophagitis can be subdivided into two groups: those with likely gastroesophageal reflux disease if <20 eos/hpf and no food allergies, and others with allergic eosinophilic esophagitis associated with food allergies and often with >20 eos/hpf.

Eosinophilic Gastroenteritis Epidemiology, Diagnosis and Management

Eosinophilic gastroenteritis is a heterogeneous and uncommon disorder characterized by eosinophilic inflammation of the gastrointestinal tissues. The location and depth of infiltration determine its varied manifestations, and the latter is also the basis for the proposed classification into mucosal, muscular and serosal eosinophilic gastroenteritis. Abdominal pain, vomiting, and diarrhea are each present in nearly 50% of the patients, with some overlap. Peripheral eosinophilia is seen in approximately two-thirds of patients with eosinophilic gastroenteritis.It is now clear that eotaxin, a specific eosinophil chemoattractant, plays a pivotal role in the process of eosinophil production. The differential diagnosis of eosinophilic gastroenteritis in children includes parasitic infections, inflammatory bowel disease, connective tissue diseases, some malignancies and adverse effects of drugs.Eosinophilic gastroenteritis itself has been strongly associated with food allergies, and concomitant atopic diseases or a family history of allergies is elicited in about 70% of cases. The pediatric experience is unique with respect to recognition of distinctive entities such as allergic procto-colitis, almost exclusively seen in infants, and eosinophilic esophagitis being increasingly reported among children and young adults. The gold standard for diagnosis, usually demonstrated on endoscopie biopsies, is prominent tissue eosinophilia. However, the diagnosis may be obscured by the patchy nature of the disease, and muscular and serosal eosinophilic gastroenteritis subtypes. In the latter cases, full thickness biopsies would be indicated for a definitive diagnosis.There are many reports of successful treatment of eosinophilic gastroenteritis in children, using a variety of treatment regimens including elimination diets. Corticosteroids remain the most effective agents for controlling symptoms, but unfortunately the relapsing nature of the disease would mandate prolonged corticosteroid use. Reports of favorable responses to new leukotriene inhibitors in patients with eosinophilic gastroenteritis are encouraging; these responses should stimulate future research on the pathophysiology and management of eosinophilic gastroenteritis.

GASTROESOPHAGEAL REFLUX DISEASE IN CHILDREN

In the pediatric population, gastroesophageal reflux most often presents in infancy as effortless regurgitation, but pathologic GERD is accompanied by signs of malnutrition, respiratory diseases, and esophagitis or its complications. Because of the distinctive pathophysiology predisposing infants to GERD, the diagnostic approach must begin with a thorough history that determines the extent of further diagnostic tests and the course of management. Empiric therapy assumes importance in infants with GERD because of the limited differential diagnoses in consideration. Conservative therapy is of utmost importance because of the unique provocative factors in the pathophysiology of infantile GERD. Prokinetic pharmacotherapy takes precedence over acid suppression because of the more important role of motility factors compared with acid secretion in infantile GERD.

Positioning for prevention of infant gastroesophageal reflux

A controlled, prospective comparison of the use of the infant seat versus prone, head-elevated positioning in a harness was undertaken in 15 infants with gastroesophageal reflux. pH monitoring of the distal esophagus demonstrated less reflux in the harness than in the seat (P less than 0.001) during 19 pairs of two-hour postprandial trials. This difference was the result of both fewer episodes (P less than 0.001) and briefer episodes (P less than 0.05). Prone-elevated positioning in the harness described is superior to positioning in an infant seat in the treatment of gastroesophageal reflux in infants younger than 6 months.

Reliability and Validity of an Infant Gastroesophageal Reflux Questionnaire

To improve history-taking of infants with suspected gastroesophageal reflux, we developed an Infant Gastroesophageal Reflux Questionnaire consisting of 161 items covering demographics, symptoms (regurgitation, weight deficit, respiratory difficulties, fussiness, apnea, and pain or bleeding of esophagitis), and possible causes (feeding volume and frequency, allergy, infection, colic, central nervous system abnormalities, positioning, and smoke exposure). The questionnaire was completed by primary caretakers of 69 infants aged 1 to 58 weeks suspected of having reflux. Median time to complete the questionnaire was 20 minutes. The median internal consistency of 29 pairs of redundant questions was 0.94. Median test-retest consistency of 110 items for nine respondents was 0.88. Median interobserver consistency, evaluated for 129 items in 35 questionnaires also filled out by secondary caretakers, was 0.85. The median accuracy of four externally validated items was 1.00. This questionnaire can aid pediatricians in making decisions regarding diagnoses and treatment in this common but complex disorder.