Miele, Erasmo; Staiano, Annamaria; Tozzi, Arturo; Auricchio, Renata; Paparo, Francesco; Troncone, Riccardo
Gastroesophageal reflux disease (GERD), which is often severe and accompanied by respiratory complications, occurs with increased frequency among children with psychomotor retardation (1,2). Immobility, as well as dysfunction of the autonomic nervous system, scoliosis, and reduced amounts of swallowed saliva consequent to drooling, contribute to the pathogenesis of GERD in this group of children. There is no agreement on the most appropriate method of treating neurologically impaired patients with GERD: conventional medical management is less effective in neurologically impaired than in normal infants and children, and surgical intervention is associated with high operative risk for the poor physical conditions (3,4).
It was recently reported that chronic gastrointestinal symptoms and histologic changes of the esophagus unresponsive to standard treatments for GERD were improved by the use of elemental formulas (5). Based on these new findings, it was suggested that the differential diagnosis of pediatric patients with common gastrointestinal symptoms of refractory GERD, who have an eosinophilic infiltration of the esophageal mucosa, should include consideration of hypersensitivity to dietary proteins in addition to GERD (5).
Because neurologically impaired children are notoriously resistant to both medical and surgical therapy for GERD, the aim of our study was to evaluate the efficacy of a dietary trial in these patients, who are unresponsive to medical and/or surgical therapy, to investigate whether unremitting symptoms of GERD and abnormal biopsy results of the esophagus could be associated with the ingestion of certain foods. We also focused on a better characterization of the inflammatory infiltrate in the esophageal biopsy samples to determine whether intraepithelial parameters of inflammation, such as presence of eosinophils, neutrophils, or mast cells, may prove sensitive in detecting esophageal inflammation caused by food hypersensitivity.
PATIENTS AND METHODS
Between October 1998 and June 1999, nine consecutive patients (three boys and six girls; median age, 44 months; range, 13–180 months) affected by severe brain damage and refractory esophagitis were recruited. Nine subjects were affected by severe psychomotor retardation (intelligence quotient < 35). The most severe clinical manifestations of brain damage, related to profound perinatal or prenatal hypoxia, were associated with classic tetraplegia in six patients, severe spastic diplegia in one, and persistent hypotonia in one. The remaining patient was affected by nonspecific mild psychomotor retardation (intelligence quotient = 70).
All patients had a long-standing history of GERD (median duration, 26 months; range, 8–157 months) despite standard antireflux therapies, including H2 receptor antagonists, omeprazole, liquid antacids, and cisapride. Three of these children had undergone a surgical antireflux procedure (Nissen). Clinical characteristics of the patients are reported in Table 1. During initial symptom evaluation, an arbitrary scoring system was used for symptomatologic assessment (Table 2). Furthermore, all children underwent a cellobiose/mannitol sugar permeability test and upper endoscopy with esophageal biopsy. Seven of nine patients who completed the study underwent continuous 24-hour intraesophageal pH monitoring.
The study was approved by the local institutional review board. In each case, informed written consent for participating in the study was obtained from the children's parents.
The intestinal permeability test was performed after overnight fast, according to the previously reported method (6). In brief, each subject drank a solution containing 2 g mannitol, 5 g cellobiose, and water to make 100 mL (osmolarity, 270 mmol/L). Urine was collected for the next 5 hours and stored at −20°C. The subjects went without food during the test but were allowed to drink water after the first hour.
The final ratio of percentage recovery of cellobiose to percentage recovery of mannitol was calculated. A cellobiose:mannitol ratio greater than 0.022 was considered abnormal, as the value exceeded 2 SD over the mean derived from 50 age- and sex-matched normal children (6).
Endoscopy and Histology
Upper intestinal endoscopy was performed by the same endoscopist, using a pediatric fiberoptic gastroscope (Olympus GIFPQ20, Olympus Optical Co., LTD, Tokyo, Japan) with a 2.8-mm diameter bioptic channel. The forcep biopsy specimens were obtained from macroscopically diseased areas, if present, or from the distal normal esophageal mucosa, 2 cm to 3 cm above the gastroesophageal junction. During endoscopy, macroscopic changes of esophageal mucosa were evaluated according to the scale reported in Table 3. However, the diagnosis of esophagitis was always based on histologic criteria in biopsy specimens obtained during endoscopy (Table 3).
Esophagitis was graded according to methods previously reported (7,8). In addition to the histologic parameters reported in Table 3, the number of mucosal mast cells in the esophageal biopsy specimens was determined for each subject. Histology was graded by an observer blinded to the endoscopic findings.
If macroscopic abnormalities were noted on gross examination of the esophageal mucosa at endoscopy, a minimum of two biopsy specimens were obtained from the abnormal areas. If the esophageal mucosa appeared normal, two biopsy specimens were obtained from the distal esophagus, at least 3 cm to 4 cm above the gastroesophageal junction. At least one biopsy specimen was oriented on filter paper and fixed in 10% buffered formalin. The biopsy specimens were subsequently sectioned perpendicular to the mucosal surface and stained with hematoxylin and eosin. Furthermore, at least one biopsy specimen was oriented and immediately embedded in frozen section medium (Tissue-Tek, OCT Compound, Sukura Finrtek Europe, The Netherlands), frozen, and stored in liquid nitrogen for immunohistochemical studies.
Prolonged pH Measurement
Prolonged 24-hour intraesophageal pH examination was performed with a portable digital recorder (Digitrapper II; Synectics, Medtronic Gastrointestinal, Synectics Medical AB, Stockholm, Sweden) connected to a flexible antimonium probe (Zinectics 24; Medtronic Functional Diagnostics Zinectics, Inc, U.S.A.). At the beginning of the study, the pH meter was calibrated with a standard solution of pH 4 and 7. Subsequently, a pH electrode was inserted via the nose, with the tip placed at 87% of the distance from the nares to the lower esophageal sphincter, according to the technique of Strobel et al. (9). The following parameters were analyzed: percentage of time with pH less than 4, total number of reflux episodes, number of episodes lasting more than 5 minutes, mean duration of reflux episodes, and duration of longest episode. A gastroesophageal reflux episode was defined as a decrease in the distal esophageal pH less than 4 for more than 20 seconds, and pH measurement was considered pathologic when total acid esophageal exposure time was greater than 4% (10).
The diagnosis of GERD was based on the microscopic changes of the esophagus. Before the dietary trial, no patients had allergy history or skin test–positive food antigens. Before and after the dietary trial, symptomatology, endoscopy, and histology were graded using scales reflecting increasing severity with increasing grade.
After the initial evaluation, all children were fed the elemental formula Neocate (SHS-Nutricia, Italy) by mouth or nasogastric tube for a minimum of 4 weeks, during which time the previous treatments for GERD were allowed. The quantity of the administered elemental formula was calculated on the basis of a daily energy intake of 1.1 times the resting energy expenditure; energy intake was subsequently adjusted on the basis of changes in weight and adiposity (11). One patient took the formula only by mouth, five patients took the majority of their formula orally with some enteral tube supplementation, and three patients took the formula exclusively by home-based nasogastric tube feedings. No other solid foods or other sources of complex dietary proteins were permitted during the dietary trial. Symptomatology, weight gain, hydration state, and tolerance of the formula were monitored and recorded at regular intervals.
After the dietary trial, each child underwent endoscopy with biopsy of the distal esophagus and a cellobiose/mannitol sugar permeability test.
After completion of the post–dietary trial endoscopy, the parents were instructed to reintroduce one source of protein at a time to their children in an open fashion and to record any symptoms observed after the reintroduction of the food. After 6 months from the end of the dietary trial, long-term symptoms were still remitted in all patients who were fed a diet without cow's milk protein.
Predietary and postdietary scores of symptoms, endoscopy, and histology were compared using the nonparametric Wilcoxon signed rank test. Statistical significance of the improvement in symptoms, endoscopy, and histology scores, and in the cellobiose/mannitol sugar permeability test prevalence was performed with the Fisher exact test. A P value < 0.05 was considered significant.
The pretreatment of severity of esophagitis assessed by endoscopy in the nine patients who completed the study, esophagitis during the predietary period, as determined by endoscopy, was severe in two patients, moderate in five, and mild in two. Histologically determined esophagitis was moderate in seven patients and mild in two. Because intraepithelial eosinophils in the esophageal mucosa was one of the criteria for defining the severity of esophagitis, the increasing presence of intraepithelial eosinophils paralleled (P < 0.05) the severity of the esophagitis. Using a test cut-off of 0.022, the sugar permeability test result was abnormal (range, 0.038–0.068) in five of nine patients (55.5%), but no one had allergy history or skin test–positive food antigens. Results of continuous 24-hour intraesophageal pH monitoring were abnormal in five of seven patients with a mean ± SD total acid esophageal exposure time of 9.5% ± 6.1%.
During the postdietary period, seven of nine patients (77.7%) experienced resolution of their chronic complaints (Fig. 1).
Moreover, all patients showed a significant (P < 0.01) weight gain, with a mean ± SD increase of 0.862 kg ± 0.624 kg. Both endoscopic and histologic findings significantly (P < 0.01 and P < 0.005, respectively; Fisher exact test) improved in comparison with pretrial values (Fig. 2). No significant changes were observed in the number of esophageal mucosal eosinophils and mast cells in predietary and postdietary esophageal biopsy specimens (Fig. 3). After the trial, permeability sugar test results normalized in three of five patients (60%).
Open challenge with specific food re-created symptoms identical to those experienced before the dietary trial in seven of nine patients (77.7%). Reintroduction of cow's milk proteins was responsible of the reappearance of the symptomatology in all seven patients. Gradual reintroduction of other food, such as potatoes, chicken, and lamb, did not cause reappearance of symptoms.
At 6 months of follow-up, all nine patients fed a diet without cow's milk proteins were free of symptoms.
We evaluated the efficacy of the elemental formulas on refractory esophagitis in children with cerebral palsy. Chronic gastrointestinal symptom control was documented, as was endoscopic and histologic improvement of the esophagitis, in patients who were previously unresponsive to conventional antireflux treatments. In our patients, a variety of long-term common gastrointestinal symptoms, such as abdominal pain, poor appetite, poor weight gain, and vomiting, as well as symptoms of respiratory chronic aspiration, which were unresponsive to standard antireflux therapies, including Nissen fundoplication, improved within few days from the beginning of the elemental formulas. Most of these symptoms reappeared with the reintroduction of cow's milk protein in the diet. Based on the correct diagnosis of cow's milk protein allergy (CMPA), established by therapeutic trial, at least 77.7% of our patients with refractory esophagitis seemed to have concurrent cow's milk intolerance.
CMPA has been reported to be associated with GERD in 16% to 30% of neurologically normal children (6,12). In 1985, Forget and Arends suggested that all cases of intractable GERD should be suspected of CMPA and investigated accordingly (13). Indeed, whereas neurologically impaired children are notoriously resistant to both medical and surgical treatment of GERD, to our knowledge there is no study on the association of CMPA and GERD in this subgroup of patients. The fact that elemental formulas determined a significant improvement in the long-term symptomatology, as well in the endoscopic and histologic findings of the esophagitis, and the reappearance of symptoms in 77.7 of our patients after challenge with cow's milk proteins support the hypothesis that GERD is associated with CMPA in this subgroup of patients.
The clinical presentation of these patients with GERD and CMPA did not differ from that observed in those with GERD only. Furthermore, no specific laboratory test, apart from the permeability test, proved to be useful in discriminating these two group of patients (6). Circulating eosinophils, total serum immunoglobulin E, and skin test results were all unremarkable in these patients. However, the permeability test result was abnormal in 56% of our patients before the dietary trial, and it normalized in 60% of them after the dietary trial. Intestinal permeability tests are not commonly used in the diagnosis of cow's milk intolerance, although the enteropathy associated with this disorder would be expected to have an effect on such studies (6). Nonatopic infants with food protein intolerance have recently been reported to show a significant reduction of distressed behavior and symptoms of GERD by treatment with amino acid–based infant formula (14).
Although previous studies have stressed the clinical significance of an eosinophilic infiltrate in esophageal biopsy specimens from patients with peptic esophagitis, recent reports of patients with refractory esophagitis suggest that an eosinophilic infiltrate is more common in esophageal biopsy specimens from patients with allergic disorders than from children with peptic esophagitis (5,15). In addition, it has been suggested that the presence of mucosal mast cells could distinguish allergic from GERD-induced esophagitis (16). Eosinophils could be attracted to the esophagus by cytokines produced by local or distant mast cells. In our study, although a decrease in intraepithelial eosinophils was observed after the dietary trial, no statistical significance was reached. Furthermore, the presence of mucosal mast cells in the esophageal biopsy specimens did not change between the predietary and postdietary periods. The persistence of eosinophilic infiltration of the esophageal mucosa after the dietary trial may be the continuous expression of a histologic marker of esophagitis, which could require more than 4 weeks of dietary trial to disappear.
The lack of strict correlation between the disappearance of markers of allergic inflammation and the success of the trial with elemental diet suggest that other factors may play a significant role. A decrease in gastric emptying time and episodes of regurgitation has been reported in children with spastic quadriplegia when fed a whey-based formula (17). In our patients, we did not evaluate the gastric emptying time before and after the dietary trial, but in four patients in whom we evaluated the scintigraphic gastric emptying of liquid food before the dietary trial, it was normal. Another possibility to explain the success of the dietary trial is a direct effect of the improved nutritional status. In fact, nutritional rehabilitation as well as the use of nasogastric or gastrostomic feeding has been reported to have a positive impact on GERD (18,19). However, in our experience with a larger series of neurologically handicapped children, it seems that improved nutritional status does not appear to have an impact on the severity of GERD (unpublished data). GERD could contribute to malnutrition in neurologically impaired children much more than be a consequence of it. A course of only nasogastric or gastrostomic feeding does not appear to significantly decrease the severity of GERD: most of our patients had enteral feeding before the use of the elemental formulas, without any improvement of long-standing gastrointestinal and respiratory symptoms.
In conclusion, our data show that, in neurologically impaired children unresponsive to conventional antireflux treatments, a course of highly restricted diet with an amino acid–based formula may bring an immediate and sustained improvement in GERD symptoms. The mechanisms underlying these observations remain to be determined, and further studies should establish if these findings are necessarily of immunologic nature. The suggestion for the clinical practice is that, in neurologically impaired children presenting with symptoms typical of GERD who are unresponsive to standard antireflux treatment, a trial with elemental diet should be offered before the decision is made to perform a surgical antireflux procedure.
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