van der Pol, Rachel J.*; Loots, Clara M.*; Peeters, Laura*; Vandenplas, Yvan†; Hauser, Bruno†; Devreker, Thierry†; Omari, Taher I.‡; Benninga, Marc A.*; van Wijk, Michiel P.*
Gastroesophageal reflux disease (GERD) is common in infants and small children. Reflux esophagitis (RE) is a complication of GERD in infants and children, and diagnosis is based on endoscopically visible mucosal breaks (1). Several scoring systems for these macroscopic abnormalities are available, of which the Los Angeles classification is used most commonly. Histology findings are quite nonspecific, but biopsies are nevertheless routinely performed to confirm or rule out other pathologies, such as eosinophilic esophagitis (1). Adult patients with GERD without macroscopic evidence of RE are classified to suffer from nonerosive reflux disease (NERD) (2). It is, however, largely unclear which of the pediatric patients with GERD are at risk for RE. Reliable patient selections or predictions of endoscopic findings cannot be made based on symptoms nor pH-metry (3–7). In addition, a recent study in children using combined pH and multichannel intraluminal impedance monitoring (pH-MII) showed similar numbers of acid reflux, weakly acid reflux and alkaline reflux episodes, similar numbers of liquid and gas reflux episodes, and similar reflux indices (percentage of time that pH is below 4 in the esophagus) in children with and without histologic evidence of esophagitis (8).
Symptom association probability (SAP) scores based on pH-MII results are commonly used to establish a causal relation between reflux episodes and symptoms (9–12). MII baseline values have been reported to be indicative of esophageal wall conductance and are potentially a novel marker for esophageal mucosal integrity (13,14). This new paradigm is based on the fact that MII measures the resistance against alternating current. When the esophagus is at rest, MII electrodes are in contact with the esophageal wall and the impedance measured is consequently a result of the integrity of the mucosa. It is hypothesized that MII baselines are lowered in the case of esophagitis because of a lower resistance of the inflamed mucosal wall. Therefore, MII baselines could potentially contribute to select patients at risk for RE.
In the present study, we aimed to determine any association between SAP and MII baselines as well as conventional pH-MII results on the one hand and macroscopic endoscopy findings and histology on the other in children with GERD.
All of the infants and children (ages 0–18 years) with symptoms of GERD who underwent endoscopy (including biopsies) and pH-MII in the Academic Centre of the Free University in Brussels, Belgium, between 2007 and 2009 were studied retrospectively. Children with eosinophilic esophagitis, cow's milk allergy, cystic fibrosis, anatomic malformations of the gastrointestinal tract, and neurologic or metabolic disease were excluded. In addition, patients were excluded when endoscopy and pH-MII were performed >3 months apart, when they used antireflux medication during 1 of the 2 diagnostic tests or when recording errors occurred during pH-MII. If patients used antireflux medication during both endoscopy and pH-MII, they were included for all of the analyses but not for those regarding MII baseline values because proton pump inhibitors (PPIs) are known to increase these baselines (14).
During endoscopy, macroscopy was described using the Los Angeles classification and considered positive when esophagitis grade A or higher was present (15). Throughout the present study, these patients will be referred to as having RE.
Biopsies were taken as per standard operating procedure at approximately 3 cm proximal to the cardia and assessed by a pathologist specialized in pediatric gastroenterology. Histology was considered suggestive for esophagitis, and hence positive, when basal zone hyperplasia, papillar lengthening, or an increased number of neutrophils and/or lymphocytes were found (16).
All of the patients were intubated with an age-appropriate (infant/pediatric/adult) combined pH-MII catheter (Unisensor, Attikon, Switzerland). pH-MII was monitored for 24 hours and symptoms were recorded with an Ohmega data logger (MMS, Enschede, The Netherlands). All of the tracings were manually scanned for artifacts, which were excluded before analysis. Subsequently, tracings were analyzed by MMS automated analysis, software version 8.18 (MMS, Enschede, The Netherlands).
Conventional pH-MII Parameters
The reflux index (RI); the percentage of total time esophageal pH was <4; and number of acid (pH <4), weakly acid (4 ≤ pH < 7), and weakly alkaline (pH ≥7) episodes were extracted from the software (17). In infants, RI was considered positive when >10%(17). For older children, according to the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines, RI was considered normal when <3%, intermediate when between 3% and 7%, and positive if >7% (18). The numbers of weakly acid and weakly alkaline reflux events were combined and are described as the number of nonacid reflux episodes. Because no reference values are available in children, the numbers of acid and nonacid reflux episodes were analyzed as a continuous variable. The SAP was calculated by the automated software, based on the relation between symptoms and all of the reflux episodes. Furthermore, an additional SAP was calculated solely based on acid reflux episodes, the acid-SAP, because it has been shown that histology suggestive for esophagitis is associated with acid reflux (4). SAP and acid-SAP were considered positive when 95% or higher (9,10). In infants, overall pH-MII result was considered positive when RI ≥10% and/or SAP ≥95%. In older children, overall pH-MII was positive when RI ≥3% and/or SAP ≥95%. All other patients are referred to as having a normal (negative) pH-MII result.
For the first 10 patients, we analyzed MII baselines in 2 ways. First, we analyzed the data with a purposely designed Matlab-based algorithm (MathWorks, Natick, MA). This algorithm automatically excludes sudden drops and rises in impedance values and has been published previously (19). In short, this algorithm excludes all of the data samples >5000 Ω, and calculates the nadir impedance point per 10 seconds. Mean and standard deviation (SD) of these points are calculated for every 10-minute interval and samples below or above 1 SD of the mean are excluded. Again, the mean is calculated of the remaining samples. Of all the means of every 10-minute interval, the median is calculated giving an estimation of the baseline value of the complete measurement.
We tested the accuracy of this algorithm by exporting raw MII data of the most distal MII segment, with a frequency of 1 Hz, into a Microsoft Excel 2010 file. We manually excluded all the data-points that were part of a previously detected reflux episode. In addition, we excluded all of the data points with a value of >5000 Ω and those during meals. The median value of the remaining data-points was calculated.
Based on an excellent correlation (Pearson r >0.999, P < 0.001, intraclass correlation coefficient 0.988, P < 0.001), all of the remaining analyses were performed by the Matlab algorithm only. We report the baseline values as calculated by this algorithm.
For the purpose of comparing baselines with endoscopy, patients were divided in 3 different groups: patients with normal macroscopy and negative overall pH-MII; patients with normal macroscopy and with positive overall pH-MII; and patients with RE.
All of the statistical analyses were performed with SPSS 18 (SPSS Inc, Chicago, IL). Normally distributed data are shown as mean ± SD. Medians (range) are given when normal distribution could not be assumed. For the association between macroscopic and histologic outcome (dichotomous), odds ratio (OR) and confidence interval (CI) were determined.
For associations between MII baselines and conventional pH-MII parameters, a linear regression model was used with MII baselines as dependent variable. For associations between endoscopy and conventional pH-MII parameters as well as MII baselines, logistic regression analysis was performed. Outcomes of endoscopy (macroscopy and histology) were analyzed as dependent variables, and outcome of pH-MII, RI, and SAP, number of reflux episodes, and MII baseline values as independent variables. pH-MII, RI, and SAP were analyzed as dichotomous variables, the latter two as continuous variables as well. Other parameters were analyzed as continuous variables. For comparison of MII baseline values between groups a Kruskal-Wallis test was used. Comparisons of MII baselines in different segments throughout the esophagus were performed using Wilcoxon signed rank test. A P value <0.05 was considered statistically significant.
A total of 103 children underwent endoscopy as well as pH-MII during the study period. Of these, 63 children were excluded because of the time frame between endoscopy and pH-MII being >3 months (n = 24), technical problems with pH-MII recordings (n = 9), inconsistent use of medication (n = 23), and comorbidities (n = 7). The remaining 40 children had a median age of 26.5 months (2 months–16.2 years). Fourteen (35%) were infants (12 months’ old or younger). Median time between endoscopy and pH-MII was 0 (0–34) days. Eight children used PPI during both endoscopy and pH-MII measurement and were consequently excluded only from the analyses regarding MII baselines.
RE was diagnosed in 13 of 40 (32.5%) patients. Two (15%) of these were infants. Of the patients with RE, 9 (69%) patients also had histology findings suggestive for esophagitis. Yet another 11 patients (5 infants) had histology findings suggestive of esophagitis, however, without RE. No correlation was found between histology and macroscopic findings (OR 3.273, 95% CI 0.802–13.350).
Conventional pH-MII Parameters
In the 14 infants, median RI was 5.25% (0.00–19.8), and 2 (14%) had an RI ≥10% and a positive SAP. The median number of acid and nonacid reflux episodes was 36 (1–129) and 76 (8–169), respectively. The overall pH-MII result was positive in 4 infants.
In the older children, median RI was 3.85% (0.10–13.6); 11 patients had a normal RI (<3%), 9 patients intermediate (3% ≤ RI ≥ 7%), and 6 patients an abnormal RI (≥7%.). Two had a SAP >95%, of which 1 had an RI ≥3. The median number of acid and nonacid reflux episodes was 17 (2–102) and 83 (8–214), respectively. The overall pH-MII result was positive in 16 children.
For the 32 patients who did not receive PPI treatment during endoscopy and pH-MII monitoring, the mean baseline of the most distal segment was 2812 ± 920 Ω. Baselines were 3154 Ω (2050–4411) in group 1 (n = 11), 2612 Ω (1341–4567) in group 2 (n = 9), and 2778 Ω (767–3570) in group 3 (n = 12), for the most distal segment (Fig. 1).
Associations Between MII Baselines and Conventional pH-MII Parameters
A significant association was found between MII baselines in the most distal esophageal segment and RI (P = 0.009, B = −125.65, Fig. 2). No associations were found between MII baselines and SAP, nor between MII baselines and the number of acid and/or nonacid reflux episodes.
In patients with a positive overall pH-MII result, a significant difference was found between MII baselines in the distal esophagus compared with baselines of the most proximal MII segment (Fig. 3). In patients with negative conventional pH-MII results, no such difference was found.
Associations Between pH-MII and Endoscopic Findings
Associations Between Conventional pH-MII Parameters and Endoscopic Findings
Nine of the 13 patients (69.2%) with RE had an overall positive pH-MII result. Associations between pH-MII results and endoscopy findings are shown in Table 1.
Thirteen of the 20 (65%) patients with histology suggestive of esophagitis had an overall positive pH-MII result. No associations were found between conventional pH-MII parameters and histology findings (Table 1). Analysis based on acid-SAP showed no association between acid-SAP and histology nor between acid-SAP and the presence of RE (data not shown).
Associations Between MII Baselines and Endoscopic Findings
No significant associations were found when baselines were entered in the logistic model together with the conventional pH-MII parameters (P = 0.366, OR 0.999 for RE and 0.997, OR 1.000 for histology suggestive for esophagitis). No statistical difference was found between baselines in groups 1 to 3 (Fig. 1), neither for the difference between the proximal and distal esophagus (data not shown). In children with RE or histology suggestive of esophagitis, MII baselines did not differ significantly (P = 0.099 and P = 0.255, respectively) between the proximal and distal esophagus (Fig. 3).
This is the first study to assess the relation between novel pH-MII parameters and endoscopy findings in children with GERD. MII baselines have been suggested to be indicative of mucosal integrity (13); however, we did not find a relation between MII baselines and endoscopy findings. Nevertheless, MII baselines were significantly higher in patients with a lower RI. In addition, we found that distal MII baselines differ significantly from proximal MII baselines in children with a positive overall pH-MII result. MII baselines have been calculated differently by different groups (13,14,23). We recently published an algorithmic analysis method to calculate baseline values (19). In the present study, we show a perfect correlation with manual subanalysis. This algorithm has the significant advantage of being far less time-consuming and not subject to observer variability and bias as all of the previously used methods were.
In adult patients with RE, the visible disruption of the mucosa and inflammatory exudate results in electrical potential difference of the esophagus (20), causing lower baselines (13,21,22). In adult patients with NERD, esophageal integrity is disturbed by dilated intercellular spaces, which has been shown to result in lower baselines as well (13,22,23). For the so-called patients with NERD in the present study (group 2), we did not find these lowered baselines.
The found difference in the proximal and distal esophagus is interesting because acid exposure in the distal esophagus is associated with low baselines in the distal and proximal esophagus in adults (22,24). Our results may be the result of increased local damage after acid exposure, which occurs more often in the distal esophagus.
SAP scores showed a significant association with RE; however, the clinical significance of this finding is disputable, given the odds ratio of 1.018 (95% CI 1.001–1.035). This result, although novel in children, is not entirely surprising because many studies have tried and failed to reliably correlate endoscopy findings with clinical symptoms (3,25–27). Moreover, previous pH-metry studies have reported inconsistent associations (6,7,28), and the one study using pH-MII in children found no association between conventional pH-MII parameters and histology (8).
There are some drawbacks to our study. First, it was retrospectively designed and of a small sample size. We have tried, however, to prevent selection biases as much as possible by including all of the children who underwent endoscopy and pH-MII. Second, the thing that limits all of the studies using MII baselines is the absence of normal values for MII parameters. Cutoff points were therefore chosen based on common practice in infants and established best practice guidelines (European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition) in older children (18). In addition, the use of automated analysis to analyze MII data is thought to be inferior to manual readings by some; however, we have recently demonstrated large inter and intraobserver variability amongst pH-MII analyses performed by experts in the field and this suggests that automated analysis may in fact be more reliable (29).
Last, PPI therapy, has been shown to increase MII baseline, both in children and in adults (14,23). It would therefore be interesting to test MII baselines and perform endoscopy in patients with RE before and after PPI therapy to evaluate whether healing of RE coincides with an increase in baseline and could also be used to monitor treatment effect.
In conclusion, MII baselines do not correlate with endoscopic findings, and although there is an association between SAP and RE, the clinical value of this is limited. Nevertheless, some acid-related parameters show a relation with baseline values and we found a perfect correlation between manual and automated analysis of MII baselines. Large prospective studies should be performed to establish the exact clinical role of MII baselines in pediatric patients with GERD with and without RE. The perfect correlation between an automated MII baseline calculation and manual analysis largely enhances the possibilities of performing such studies.
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