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The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children
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MODEL
Pediatrics and Neonatology (2016) xx, 1e5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.pediatr-neonatol.com
ORIGINAL ARTICLE
The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children Yu-Wen Liu a, Jia-Feng Wu a, Huey-Ling Chen a, Hong-Yuan Hsu a, Mei-Hwei Chang a, Wei-Chung Hsu b, Ping-Huei Tseng c, Hsiu-Po Wang c, Yen-Hsuan Ni a,* a Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan b Department of Otolaryngology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan c Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
Received Apr 2, 2015; received in revised form Jun 26, 2015; accepted Sep 18, 2015
Available online - - -
Key Words esophageal impedance; gastroesophageal reflux; reflux esophagitis
Background: Gastroesophageal reflux (GER) is the retrograde flow of gastric contents into the esophagus and may induce a variety of complications. Endoscopically visible breaks in the distal esophageal mucosa are the most reliable evidence of reflux esophagitis. Combined multichannel intraluminal impedance and pH-metry (MII-pH) is a technique that enables monitoring of GER independent of its acidity. The aim of this study is to investigate the GER patterns in children with the aid of MII-pH monitoring and determine the correlation between endoscopically proven reflux esophagitis and reflux types by MII-pH monitoring. Methods: One hundred and twenty children were enrolled from January 2010 to October 2011 for MII-pH monitoring. We studied the GER patterns by means of pH (acid and nonacid reflux) and composition (liquid, mixed, and gas reflux) by the esophageal MII-pH signals. Meanwhile, 34 (28.3%) patients received esophagogastroduodenoscopy examination at the same time. The severity of reflux esophagitis was graded with Los Angeles classification. Results: MII-pH monitoring significantly increased the detection of numbers of reflux compared with traditional 24-hour pH monitoring (p < 0.001). The significant cutoff value of MII-pH parameters including DeMeester score 21, duration of longest acid reflux 17 minutes, and occurrence of acid reflux for more than 5 minutes showed good correlation in the prediction
* Corresponding author. Department of Pediatrics, National Taiwan University Children’s Hospital, National Taiwan University, Number 8, Chung Shan South Road, Taipei 100, Taiwan. E-mail address: [email protected] (Y.-H. Ni). http://dx.doi.org/10.1016/j.pedneo.2015.09.008 1875-9572/Copyright ª 2015, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Liu Y-W, et al., The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2015.09.008
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Y.-W. Liu et al of the presence of endoscopic reflux esophagitis. The odds ratios of the above mentioned parameters were 12.6, 8.94, and 7.5, respectively (p Z 0.02, p Z 0.01, and p Z 0.01). Furthermore, 3 episodes per day of acid reflux for more than 5 minutes can predict the occurrence of severe reflux esophagitis (odds ratio 12.78, p Z 0.009). Conclusion: MII-pH monitoring not only raised the diagnostic yield in identifying GER, but it also showed significant correlation with the presence of endoscopically proven reflux esophagitis in children. Copyright ª 2015, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
1. Introduction Gastroesophageal reflux disease (GERD) in children has been defined as troublesome symptoms and/or complications caused by reflux of gastric contents into the esophagus.1 It affects as much as 30% of the pediatric population and is by far the most common disease caused by abnormality in esophageal motility.2 Clinical features of GERD in infants and children are quite variable. The gastrointestinal and extraesophageal symptoms vary among individuals and may change by age. Reflux esophagitis, represented with endoscopically visible breaks in the distal esophageal mucosa, is the most common consequence of esophageal injury caused by acid reflux.3 Combined multichannel intraluminal impedance and pHmetry (MII-pH) is a relatively novel technology to detect intraluminal bolus movement and is considered the best method that can achieve high sensitivity for detecting all types of reflux episodes regarding acidity (acidic, weakly acidic, weakly alkaline) and composition (liquid, gas, mixed).4 Previous studies did not provide a distinct parameter of MII-pH results to predict esophageal mucosal injury in children.5 The aim of the present study is to investigate the GER pattern in children with the aid of MIIpH monitoring and to determine the correlation between reflux esophagitis proven by endoscopy and reflux patterns by MII-pH monitoring.
2. Patients and method 2.1. Study participants From January 2010 to October 2011, 120 consecutive patients recruited from the Departments of Pediatrics and Otolaryngology, National Taiwan University Hospital were prospectively enrolled. The mean age of this study population was 4.6 years, ranging from 6 days to 18 years at the time of investigation. The patients were referred for evaluation due to either respiratory symptoms/signs (cough, asthma, hoarseness, stridor) or gastrointestinal diseases (nausea, vomiting, regurgitation, dysphagia, heartburn sensation). None had gastric outlet obstruction, small bowel obstructive lesion, or gastrointestinal tract malrotation. In addition to the evaluation of GERD, upper gastrointestinal tract anatomical lesion, and associated esophageal motility disorder, 34 (28.3%) patients received
esophagogastroduodenoscopy (EGD) for macroscopic examination, histologic specimen confirmation, and standard operating procedure before performing percutaneous endoscopic gastrostomy. All of the endoscopic findings were recorded including the appearance of endoscopic esophagitis. The severity of reflux esophagitis was graded according to the Los Angeles (LA) classification.6 The study protocol was approved by the Institutional Review Board of the National Taiwan University Hospital, and the patients themselves or their guardians provided signed informed consent for clinical data analysis.
2.2. Twenty four-hour MII-pH investigation and analysis procedure All patients received 24-hour combined MII-pH monitoring with a single pH and eight-ring electrodes catheter (Z61A pHersaflex Disposable Internal Reference Impedance þ pH Catheters, Sierra Scientific Instruments, CA, USA) and tolerated it well. Before the procedure, the catheter was calibrated using buffered solutions of pH 4.0 and 7.0 as specified by the manufacturer (MMS, Enschede, The Netherlands). The catheter was introduced transnasally through the esophagus and the pH sensor was placed about 3 cm above the gastroesophageal junction, which was confirmed with esophageal manometry, radiography, or transnasal EGD. Patients were on a regular diet during the investigation period. The frequency of meals, body position, and related symptoms were recorded. Impedance and pH data were stored in a digital data-logger (Ohmega, MMS, Enschede, The Netherlands) using a simple frequency of 50 and 1 Hz, respectively.7 An acid reflux was defined as a drop in intraesophageal pH 4 for 5 seconds or more. DeMeester score was calculated.8 DeMeester score greater than 14.72, upper limit of normal (95th percentile), was defined as abnormal. The parameters obtained from pH monitoring included the total number of reflux episodes, the number of reflux episodes lasting > 5 minutes, the duration of the longest reflux episode, and the reflux index (RI), which means the percentage of the entire record that esophageal pH is < 4.0. An RI > 7% was considered abnormal, an RI < 3% as normal, and an RI between 3% and 7% as indeterminate.9 Each MII tracing was automatically analyzed using the package analytic software (MMS software 8.19, MMS, Enschede, The Netherlands) and was then reviewed manually. A liquid reflux was defined as a fall in impedance
Please cite this article in press as: Liu Y-W, et al., The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2015.09.008
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Intraluminal Impedance-pH Monitoring in Children 50% from baseline in at least two consecutive channels in an aboral direction. A gas-only reflux was defined as a simultaneous increase in impedance > 3000 ohms in any two consecutive impedance sites, with one site having an absolute value > 7000 ohms. A mixed reflux met both the liquid and the gas criteria.10 The nonacid reflux events comprised weakly acid reflux with pH values between 4 and 7 and weakly alkaline reflux with pH nadir not dropping below 7.4
2.3. Statistical analysis Data were collected and analyzed using small STATA version 8.0 (StataCorp LP, TX, USA). All continuous data were presented as mean and standard deviation. Comparisons between groups were performed using Student t test. Categorical variables were compared using logistic regression analysis. Receiver operating characteristic (ROC) analysis was performed to assess the predictive power of various MII-pH variables. The ROC curves were calculated along with 95% confidence intervals. A p value < 0.05 was considered to be statistically significant.
3. Results 3.1. General characteristics Demographic data and clinical presentation of the patients including subgroups of infants and children are shown in Table 1. One hundred and twenty patients (68 boys) were enrolled with a mean age of 4.6 5.3 years (range: 6 days to 18 years). Among the study group, 49 (40.8%) patients had underlying respiratory disease, of whom 11 (9.2%) had a tracheostomy and 23 (19.2%) had the diagnosis of aspiration pneumonia during the 3 months prior to entering this study. Three (2.5%) full term infants were referred for examination due to apnea. Thirty (25%) patients had underlying neurologic disability and 21 (17.5%) had cerebral palsy. We
Table 1
General characteristics of the study patients.
Characteristics
Total Infant (n Z 120) (n Z 47)
Age (yr), mean SD Gender, n (%) Male Female Underlying respiratory disease, n (%) Aspiration pneumonia Tracheostomy Underlying neurologic disability, n (%) Cerebral palsy Patient source, n (%) Pediatric department Otolaryngology department
4.6 5.3
SD Z standard deviation.
Children (n Z 73)
68 (56.7%) 30 (63.8%) 38 (52.1%) 52 (43.3%) 17 (36.2%) 35 (47.9%) 49 (40.8%) 19 (40.4%) 30 (41.1%) 23 (19.2%) 8 (17%) 15 (20.5%) 11 (9.2%) 4 (8.5%) 7 (9.6%) 30 (25%) 11 (23.4%) 19 (26%) 21 (17.5%) 96 (80%) 24 (20%)
7 (14.9%) 14 (19.2%) 38 (80.9%) 58 (79.5%) 9 (19.1%) 15 (20.5%)
3 attempted to investigate the correlation between GER and underlying respiratory or neurologic disease. Patients enrolled from pediatric and otolaryngology departments accounted for 80% and 20% of the study population, respectively. None of the study population (n Z 120) needed intravenous sedation for MII-pH study, while 24 patients (70.6%) among those who received EGD examination (n Z 3 4) needed intravenous sedation for the procedure (RD 0.7, p < 0.001). MII-pH is a less invasive procedure than the EGD examination in children. This finding is compatible with previous reports.7
3.2. Analysis of MII-pH combined data In the 120 patients, 6785 reflux events were detected with MII-pH monitoring; of these, 2170 (32%) were acid and 4615 (68%) were nonacid reflux events. On the basis of impedance analysis, 2911 (43%) of total reflux events were liquid and 3874 (57%) were mixed in composition. Impedance probes identified significantly more reflux episodes than the pH probe in the whole study population (mean standard deviation Z 56.5 47.9 vs. 18.1 19.8 reflux episodes; 95% confidence interval: 47.9e65.2 vs. 14.5e21.7 reflux episodes; p < 0.001).
3.3. Correlation between endoscopic esophagitis and MII-pH combined data Among 34 patients who had received EGD, age distribution was from 5 months to 18 years and the male-to-female ratio was 14:20. Endoscopic reflux esophagitis was diagnosed in 19 of 34 (56%) patients. In accordance with the LA classification, there were seven (37%) patients with grade A esophagitis, four (21%) with grade B esophagitis, five (26%) with grade C esophagitis, and three (16%) with grade D esophagitis. Regarding the prediction of the presence of endoscopic reflux esophagitis, ROC analysis yielded the significant cutoff value of MII-pH variables, including DeMeester score 21, duration of longest acid reflux 17 minutes, and occurrence of acid reflux for more than 5 minutes, to reveal good predictability in our data. In applying the logistic regression model, we showed that DeMeester score 21, duration of longest acid reflux 17 minutes, and occurrence of acid reflux for more than 5 minutes were significant factors [odds ratio (OR) 12.6, OR 8.94, and OR 7.5; p Z 0.02, p Z 0.01, and p Z 0.01, respectively] in detecting the presence of endoscopic reflux esophagitis (Table 2). Concerning different treatment strategies, it is crucial to differentiate between mild (LA grade A and grade B esophagitis) and severe reflux esophagitis (LA grade C and grade D esophagitis). Furthermore, using pairwise regression we determined that the occurrence of acid reflux for more than 5 minutes was significantly correlated with severe reflux esophagitis (correlation coefficient 0.3689, p Z 0.03). The patients with mild reflux esophagitis and without esophagitis (n Z 26) had 1.88 episodes per day of acid reflux for more than 5 minutes on average, while the patients with severe reflux esophagitis (n Z 8) had 27.13 episodes per day of acid reflux for more than 5 minutes on
Please cite this article in press as: Liu Y-W, et al., The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2015.09.008
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Y.-W. Liu et al Table 2 Logistic regression of multichannel intraluminal impedance and pH-metry variables predicting the presence of endoscopic reflux esophagitis in gastroesophageal reflux children.
DeMeester score S21 vs. < 21 Longest acid reflux 17 vs. < 17 min With vs. without acid reflux > 5 min
Odds ratio
95% CI
p
12.6
1.37e115.97
0.02
8.94
1.56e51.18
0.01
7.5
1.61e34.95
0.01
CI Z confidence interval.
average. ROC analysis showed 3 episodes per day of acid reflux for more than 5 minutes could predict the occurrence of severe reflux esophagitis (OR 12.78, p Z 0.009; Figure 1).
4. Discussion MII-pH monitoring enables the detection and characterization of all types of reflux and it is supposed to provide clinically useful additional information to traditional 24hour pH monitoring for the capacity of detecting nonacid reflux, especially in infants and during postprandial periods.5 Due to the immaturity of parietal cell function in young children, the majority of reflux in young children is nonacid, which may not be able to cause mucosal injury.11 Data obtained from the present investigation clearly suggest that MII-pH significantly increases the diagnostic accuracy of the test as first-line assessment in infants and
Figure 1 Receiver operating characteristic curve for the cutoff value of episodes of acid reflux more than 5 minutes to predict the occurrence of severe reflux esophagitis. Cutoff 3; area under the curve 76.37; p Z 0.02. AUC Z area under the curve.
children with suspected GERD.12 In our study, acid reflux and nonacid reflux episodes recognized with MII-pH monitoring accounted for 32% and 68% of total reflux events, respectively, which represented in a 3-fold increase of the numbers in comparison with acid reflux episodes with pH monitoring only. These observations may be explained by two features: (1) the patients kept taking acid suppressants during the study period; and (2) the infant group accounted for up to 39.2% of the recruited study group, and infants have more nonacid reflux. The relation between reflux symptoms, endoscopic or histologic findings, and exposure of the esophagus to acid is considered to be complex.13 Previous studies tried and failed to correlate endoscopic findings with clinical symptoms reliably.14 The correlation between MII-pH parameters and endoscopic findings remains an issue.15 Now we know that the fundamental abnormality in GERD is exposure of the esophageal epithelium to reflux content, resulting in tissue injury and/or symptoms. Acid is the key element in reflux content in the production of esophagitis and/or microscopic alterations.16 According to previous studies in adults, macroscopic mucosal changes of the esophagus were more common in patients with increased acid exposure.17 However, few studies documented the correlation between endoscopic reflux esophagitis and MII-pH in pediatric patients.18 Different endoscopic grading systems applied in different ages may produce inconsistent results.19,20 Our pilot study determined the relationship between the parameters of MII-pH and the presence of endoscopic reflux esophagitis in the pediatric population. We further set up the cutoff value of DeMeester score 21, duration of longest acid reflux 17 minutes, and occurrence of acid reflux for more than 5 minutes of MII-pH variables to predict the presence of endoscopic reflux esophagitis. Different treatment strategies are suggested based on the severity of reflux esophagitis. In our study, ROC analysis yielded the optimal cutoff value of 3 episodes per day of acid reflux for more than 5 minutes to discriminate severe from mild reflux esophagitis. According to these parameters, we could apply this noninvasive method to establish useful predictors for esophagitis other than endoscopy. For the confirmation of mucosal lesions, endoscope is the diagnostic mode of choice. MII-pH parameters are potentially a novel marker for esophageal mucosal integrity.15 Therefore, the combination of MII-pH and endoscopy may achieve a better diagnostic accuracy. The possible problem of this MII-pH method is lack of normal values for all of the age groups.21,22 We made a subgroup analysis according to different ages, individual grading of reflux esophagitis, and underlying disease variables. However, these results showed no statistically significant power for comparison due to unevenly distributed case numbers in our study. The numbers of patients with different grading of endoscopic reflux esophagitis in our study were not evenly distributed due to the small sample size, which rendered us unable to exclude selection bias. This drawback could be solved if more patients are enrolled in further studies. In conclusion, our study demonstrated that MII-pH monitoring added significantly to our understanding of GER and its complications. We also illustrated the parameters of MII-pH to predict the presence of endoscopically-
Please cite this article in press as: Liu Y-W, et al., The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2015.09.008
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Intraluminal Impedance-pH Monitoring in Children proven reflux esophagitis in children. MII-pH was also a less invasive procedure than EGD because the procedure does not need intravenous sedation and has no radiation exposure. For the detection of mucosal lesion, EGD is still indicated for the complementary purpose of 24-hour MII-pH study.
5
10.
11.
Conflicts of interest The authors have no potential, perceived, or real conflict of interest.
Acknowledgments
12.
13.
This work was supported by a grant from National Taiwan University Hospital (NTUH.100-M1671).
References 1. Sherman PM, Hassall E, Fagundes-Neto U, Gold BD, Kato S, Koletzko S, et al. A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population. Am J Gastroenterol 2009;104:1278e95. 2. van Wijk MP, Benninga MA, Omari TI. Role of the multichannel intraluminal impedance technique in infants and children. J Pediatr Gastroenterol Nutr 2009;48:2e12. 3. Frazzoni M, De Micheli E, Savarino V. Different patterns of oesophageal acid exposure distinguish complicated reflux disease from either erosive reflux oesophagitis or non-erosive reflux disease. Aliment Pharmacol Ther 2003;18:1091e8. 4. Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53: 1024e31. 5. Salvatore S, Hauser B, Devreker T, Arrigo S, Marino P, Citro C, et al. Esophageal impedance and esophagitis in children: any correlation? J Pediatr Gastroenterol Nutr 2009;49:566e70. 6. Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 1999;45:172e80. 7. Wu JF, Hsu WC, Tseng PH, Wang HP, Hsu HY, Chang MH, et al. Combined multichannel intraluminal impedance and pH monitoring assists the diagnosis of sliding hiatal hernia in children with gastroesophageal reflux disease. J Gastroenterol 2013;48:1242e8. 8. Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974;62:325e32. 9. Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for
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Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr 2009;49:498e547. Shay S, Tutuian R, Sifrim D, Vela M, Wise J, Balaji N, et al. Twenty-four hour ambulatory simultaneous impedance and pH monitoring: a multicenter report of normal values from 60 healthy volunteers. Am J Gastroenterol 2004;99:1037e43. Ghezzi M, Silvestri M, Guida E, Pistorio A, Sacco O, Mattioli G, et al. Acid and weakly acid gastroesophageal refluxes and type of respiratory symptoms in children. Respir Med 2011;105: 972e8. Francavilla R, Magista ` AM, Bucci N, Villirillo A, Boscarelli G, Mappa L, et al. Comparison of esophageal pH and multichannel intraluminal impedance testing in pediatric patients with suspected gastroesophageal reflux. J Pediatr Gastroenterol Nutr 2010;50:154e60. Conchillo JM, Schwartz MP, Selimah M, Samsom M, Sifrim D, Smout AJ. Acid and non-acid reflux patterns in patients with erosive esophagitis and non-erosive reflux disease (NERD): a study using intraluminal impedance monitoring. Dig Dis Sci 2008;53:1506e12. Salvatore S, Hauser B, Vandemaele K, Novario R, Vandenplas Y. Gastroesophageal reflux disease in infants: how much is predictable with questionnaires, pH-metry, endoscopy and histology? J Pediatr Gastroenterol Nutr 2005;40:210e5. van der Pol RJ, Loots CM, Peeters L, Vandenplas Y, Hauser B, Devreker T, et al. Outcomes of endoscopy and novel pHimpedance parameters in children: is there a correlation? J Pediatr Gastroenterol Nutr 2013;56:196e200. Zhong C, Duan L, Wang K, Xu Z, Ge Y, Yang C, et al. Esophageal intraluminal baseline impedance is associated with severity of acid reflux and epithelial structural abnormalities in patients with gastroesophageal reflux disease. J Gastroenterol 2013; 48:601e10. Bredenoord AJ, Hemmink GJ, Smout AJ. Relationship between gastro-oesophageal reflux pattern and severity of mucosal damage. Neurogastroenterol Motil 2009;21:807e12. Dalby K, Nielsen RG, Kruse-Andersen S, Fenger C, Durup J, Husby S. Gastroesophageal reflux disease and eosinophilic esophagitis in infants and children. A study of esophageal pH, multiple intraluminal impedance and endoscopic ultrasound. Scand J Gastroenterol 2010;45:1029e35. Tutar E, Kutluk G, Bayrak NA, C ¸ elıkel CA, Pehlıvanoglu E, Ertem D. What is the diagnostic utility of endoscopic scoring systems in children? Turk J Gastroenterol 2013;24:22e9. Genta RM, Spechler SJ, Kielhorn AF. The Los Angeles and Savary-Miller systems for grading esophagitis: utilization and correlation with histology. Dis Esophagus 2011;24:10e7. Pilic D, Fro ¨hlich T, No ¨h F, Pappas A, Schmidt-Choudhury A, Ko ¨hler H, et al. Detection of gastroesophageal reflux in children using combined multichannel intraluminal impedance and pH measurement: data from the German Pediatric Impedance Group. J Pediatr 2011;158:650e4. Lo ´pez-Alonso M, Moya MJ, Cabo JA, Ribas J, del Carmen Macı´as M, Silny J, et al. Twenty-four-hour esophageal impedance-pH monitoring in healthy preterm neonates: rate and characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux. Pediatrics 2006;118:e299e308.
Please cite this article in press as: Liu Y-W, et al., The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2015.09.008
MODEL
Pediatrics and Neonatology (2016) xx, 1e5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.pediatr-neonatol.com
ORIGINAL ARTICLE
The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children Yu-Wen Liu a, Jia-Feng Wu a, Huey-Ling Chen a, Hong-Yuan Hsu a, Mei-Hwei Chang a, Wei-Chung Hsu b, Ping-Huei Tseng c, Hsiu-Po Wang c, Yen-Hsuan Ni a,* a Department of Pediatrics, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan b Department of Otolaryngology, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan c Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
Received Apr 2, 2015; received in revised form Jun 26, 2015; accepted Sep 18, 2015
Available online - - -
Key Words esophageal impedance; gastroesophageal reflux; reflux esophagitis
Background: Gastroesophageal reflux (GER) is the retrograde flow of gastric contents into the esophagus and may induce a variety of complications. Endoscopically visible breaks in the distal esophageal mucosa are the most reliable evidence of reflux esophagitis. Combined multichannel intraluminal impedance and pH-metry (MII-pH) is a technique that enables monitoring of GER independent of its acidity. The aim of this study is to investigate the GER patterns in children with the aid of MII-pH monitoring and determine the correlation between endoscopically proven reflux esophagitis and reflux types by MII-pH monitoring. Methods: One hundred and twenty children were enrolled from January 2010 to October 2011 for MII-pH monitoring. We studied the GER patterns by means of pH (acid and nonacid reflux) and composition (liquid, mixed, and gas reflux) by the esophageal MII-pH signals. Meanwhile, 34 (28.3%) patients received esophagogastroduodenoscopy examination at the same time. The severity of reflux esophagitis was graded with Los Angeles classification. Results: MII-pH monitoring significantly increased the detection of numbers of reflux compared with traditional 24-hour pH monitoring (p < 0.001). The significant cutoff value of MII-pH parameters including DeMeester score 21, duration of longest acid reflux 17 minutes, and occurrence of acid reflux for more than 5 minutes showed good correlation in the prediction
* Corresponding author. Department of Pediatrics, National Taiwan University Children’s Hospital, National Taiwan University, Number 8, Chung Shan South Road, Taipei 100, Taiwan. E-mail address: [email protected] (Y.-H. Ni). http://dx.doi.org/10.1016/j.pedneo.2015.09.008 1875-9572/Copyright ª 2015, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
Please cite this article in press as: Liu Y-W, et al., The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2015.09.008
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Y.-W. Liu et al of the presence of endoscopic reflux esophagitis. The odds ratios of the above mentioned parameters were 12.6, 8.94, and 7.5, respectively (p Z 0.02, p Z 0.01, and p Z 0.01). Furthermore, 3 episodes per day of acid reflux for more than 5 minutes can predict the occurrence of severe reflux esophagitis (odds ratio 12.78, p Z 0.009). Conclusion: MII-pH monitoring not only raised the diagnostic yield in identifying GER, but it also showed significant correlation with the presence of endoscopically proven reflux esophagitis in children. Copyright ª 2015, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
1. Introduction Gastroesophageal reflux disease (GERD) in children has been defined as troublesome symptoms and/or complications caused by reflux of gastric contents into the esophagus.1 It affects as much as 30% of the pediatric population and is by far the most common disease caused by abnormality in esophageal motility.2 Clinical features of GERD in infants and children are quite variable. The gastrointestinal and extraesophageal symptoms vary among individuals and may change by age. Reflux esophagitis, represented with endoscopically visible breaks in the distal esophageal mucosa, is the most common consequence of esophageal injury caused by acid reflux.3 Combined multichannel intraluminal impedance and pHmetry (MII-pH) is a relatively novel technology to detect intraluminal bolus movement and is considered the best method that can achieve high sensitivity for detecting all types of reflux episodes regarding acidity (acidic, weakly acidic, weakly alkaline) and composition (liquid, gas, mixed).4 Previous studies did not provide a distinct parameter of MII-pH results to predict esophageal mucosal injury in children.5 The aim of the present study is to investigate the GER pattern in children with the aid of MIIpH monitoring and to determine the correlation between reflux esophagitis proven by endoscopy and reflux patterns by MII-pH monitoring.
2. Patients and method 2.1. Study participants From January 2010 to October 2011, 120 consecutive patients recruited from the Departments of Pediatrics and Otolaryngology, National Taiwan University Hospital were prospectively enrolled. The mean age of this study population was 4.6 years, ranging from 6 days to 18 years at the time of investigation. The patients were referred for evaluation due to either respiratory symptoms/signs (cough, asthma, hoarseness, stridor) or gastrointestinal diseases (nausea, vomiting, regurgitation, dysphagia, heartburn sensation). None had gastric outlet obstruction, small bowel obstructive lesion, or gastrointestinal tract malrotation. In addition to the evaluation of GERD, upper gastrointestinal tract anatomical lesion, and associated esophageal motility disorder, 34 (28.3%) patients received
esophagogastroduodenoscopy (EGD) for macroscopic examination, histologic specimen confirmation, and standard operating procedure before performing percutaneous endoscopic gastrostomy. All of the endoscopic findings were recorded including the appearance of endoscopic esophagitis. The severity of reflux esophagitis was graded according to the Los Angeles (LA) classification.6 The study protocol was approved by the Institutional Review Board of the National Taiwan University Hospital, and the patients themselves or their guardians provided signed informed consent for clinical data analysis.
2.2. Twenty four-hour MII-pH investigation and analysis procedure All patients received 24-hour combined MII-pH monitoring with a single pH and eight-ring electrodes catheter (Z61A pHersaflex Disposable Internal Reference Impedance þ pH Catheters, Sierra Scientific Instruments, CA, USA) and tolerated it well. Before the procedure, the catheter was calibrated using buffered solutions of pH 4.0 and 7.0 as specified by the manufacturer (MMS, Enschede, The Netherlands). The catheter was introduced transnasally through the esophagus and the pH sensor was placed about 3 cm above the gastroesophageal junction, which was confirmed with esophageal manometry, radiography, or transnasal EGD. Patients were on a regular diet during the investigation period. The frequency of meals, body position, and related symptoms were recorded. Impedance and pH data were stored in a digital data-logger (Ohmega, MMS, Enschede, The Netherlands) using a simple frequency of 50 and 1 Hz, respectively.7 An acid reflux was defined as a drop in intraesophageal pH 4 for 5 seconds or more. DeMeester score was calculated.8 DeMeester score greater than 14.72, upper limit of normal (95th percentile), was defined as abnormal. The parameters obtained from pH monitoring included the total number of reflux episodes, the number of reflux episodes lasting > 5 minutes, the duration of the longest reflux episode, and the reflux index (RI), which means the percentage of the entire record that esophageal pH is < 4.0. An RI > 7% was considered abnormal, an RI < 3% as normal, and an RI between 3% and 7% as indeterminate.9 Each MII tracing was automatically analyzed using the package analytic software (MMS software 8.19, MMS, Enschede, The Netherlands) and was then reviewed manually. A liquid reflux was defined as a fall in impedance
Please cite this article in press as: Liu Y-W, et al., The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2015.09.008
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Intraluminal Impedance-pH Monitoring in Children 50% from baseline in at least two consecutive channels in an aboral direction. A gas-only reflux was defined as a simultaneous increase in impedance > 3000 ohms in any two consecutive impedance sites, with one site having an absolute value > 7000 ohms. A mixed reflux met both the liquid and the gas criteria.10 The nonacid reflux events comprised weakly acid reflux with pH values between 4 and 7 and weakly alkaline reflux with pH nadir not dropping below 7.4
2.3. Statistical analysis Data were collected and analyzed using small STATA version 8.0 (StataCorp LP, TX, USA). All continuous data were presented as mean and standard deviation. Comparisons between groups were performed using Student t test. Categorical variables were compared using logistic regression analysis. Receiver operating characteristic (ROC) analysis was performed to assess the predictive power of various MII-pH variables. The ROC curves were calculated along with 95% confidence intervals. A p value < 0.05 was considered to be statistically significant.
3. Results 3.1. General characteristics Demographic data and clinical presentation of the patients including subgroups of infants and children are shown in Table 1. One hundred and twenty patients (68 boys) were enrolled with a mean age of 4.6 5.3 years (range: 6 days to 18 years). Among the study group, 49 (40.8%) patients had underlying respiratory disease, of whom 11 (9.2%) had a tracheostomy and 23 (19.2%) had the diagnosis of aspiration pneumonia during the 3 months prior to entering this study. Three (2.5%) full term infants were referred for examination due to apnea. Thirty (25%) patients had underlying neurologic disability and 21 (17.5%) had cerebral palsy. We
Table 1
General characteristics of the study patients.
Characteristics
Total Infant (n Z 120) (n Z 47)
Age (yr), mean SD Gender, n (%) Male Female Underlying respiratory disease, n (%) Aspiration pneumonia Tracheostomy Underlying neurologic disability, n (%) Cerebral palsy Patient source, n (%) Pediatric department Otolaryngology department
4.6 5.3
SD Z standard deviation.
Children (n Z 73)
68 (56.7%) 30 (63.8%) 38 (52.1%) 52 (43.3%) 17 (36.2%) 35 (47.9%) 49 (40.8%) 19 (40.4%) 30 (41.1%) 23 (19.2%) 8 (17%) 15 (20.5%) 11 (9.2%) 4 (8.5%) 7 (9.6%) 30 (25%) 11 (23.4%) 19 (26%) 21 (17.5%) 96 (80%) 24 (20%)
7 (14.9%) 14 (19.2%) 38 (80.9%) 58 (79.5%) 9 (19.1%) 15 (20.5%)
3 attempted to investigate the correlation between GER and underlying respiratory or neurologic disease. Patients enrolled from pediatric and otolaryngology departments accounted for 80% and 20% of the study population, respectively. None of the study population (n Z 120) needed intravenous sedation for MII-pH study, while 24 patients (70.6%) among those who received EGD examination (n Z 3 4) needed intravenous sedation for the procedure (RD 0.7, p < 0.001). MII-pH is a less invasive procedure than the EGD examination in children. This finding is compatible with previous reports.7
3.2. Analysis of MII-pH combined data In the 120 patients, 6785 reflux events were detected with MII-pH monitoring; of these, 2170 (32%) were acid and 4615 (68%) were nonacid reflux events. On the basis of impedance analysis, 2911 (43%) of total reflux events were liquid and 3874 (57%) were mixed in composition. Impedance probes identified significantly more reflux episodes than the pH probe in the whole study population (mean standard deviation Z 56.5 47.9 vs. 18.1 19.8 reflux episodes; 95% confidence interval: 47.9e65.2 vs. 14.5e21.7 reflux episodes; p < 0.001).
3.3. Correlation between endoscopic esophagitis and MII-pH combined data Among 34 patients who had received EGD, age distribution was from 5 months to 18 years and the male-to-female ratio was 14:20. Endoscopic reflux esophagitis was diagnosed in 19 of 34 (56%) patients. In accordance with the LA classification, there were seven (37%) patients with grade A esophagitis, four (21%) with grade B esophagitis, five (26%) with grade C esophagitis, and three (16%) with grade D esophagitis. Regarding the prediction of the presence of endoscopic reflux esophagitis, ROC analysis yielded the significant cutoff value of MII-pH variables, including DeMeester score 21, duration of longest acid reflux 17 minutes, and occurrence of acid reflux for more than 5 minutes, to reveal good predictability in our data. In applying the logistic regression model, we showed that DeMeester score 21, duration of longest acid reflux 17 minutes, and occurrence of acid reflux for more than 5 minutes were significant factors [odds ratio (OR) 12.6, OR 8.94, and OR 7.5; p Z 0.02, p Z 0.01, and p Z 0.01, respectively] in detecting the presence of endoscopic reflux esophagitis (Table 2). Concerning different treatment strategies, it is crucial to differentiate between mild (LA grade A and grade B esophagitis) and severe reflux esophagitis (LA grade C and grade D esophagitis). Furthermore, using pairwise regression we determined that the occurrence of acid reflux for more than 5 minutes was significantly correlated with severe reflux esophagitis (correlation coefficient 0.3689, p Z 0.03). The patients with mild reflux esophagitis and without esophagitis (n Z 26) had 1.88 episodes per day of acid reflux for more than 5 minutes on average, while the patients with severe reflux esophagitis (n Z 8) had 27.13 episodes per day of acid reflux for more than 5 minutes on
Please cite this article in press as: Liu Y-W, et al., The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2015.09.008
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Y.-W. Liu et al Table 2 Logistic regression of multichannel intraluminal impedance and pH-metry variables predicting the presence of endoscopic reflux esophagitis in gastroesophageal reflux children.
DeMeester score S21 vs. < 21 Longest acid reflux 17 vs. < 17 min With vs. without acid reflux > 5 min
Odds ratio
95% CI
p
12.6
1.37e115.97
0.02
8.94
1.56e51.18
0.01
7.5
1.61e34.95
0.01
CI Z confidence interval.
average. ROC analysis showed 3 episodes per day of acid reflux for more than 5 minutes could predict the occurrence of severe reflux esophagitis (OR 12.78, p Z 0.009; Figure 1).
4. Discussion MII-pH monitoring enables the detection and characterization of all types of reflux and it is supposed to provide clinically useful additional information to traditional 24hour pH monitoring for the capacity of detecting nonacid reflux, especially in infants and during postprandial periods.5 Due to the immaturity of parietal cell function in young children, the majority of reflux in young children is nonacid, which may not be able to cause mucosal injury.11 Data obtained from the present investigation clearly suggest that MII-pH significantly increases the diagnostic accuracy of the test as first-line assessment in infants and
Figure 1 Receiver operating characteristic curve for the cutoff value of episodes of acid reflux more than 5 minutes to predict the occurrence of severe reflux esophagitis. Cutoff 3; area under the curve 76.37; p Z 0.02. AUC Z area under the curve.
children with suspected GERD.12 In our study, acid reflux and nonacid reflux episodes recognized with MII-pH monitoring accounted for 32% and 68% of total reflux events, respectively, which represented in a 3-fold increase of the numbers in comparison with acid reflux episodes with pH monitoring only. These observations may be explained by two features: (1) the patients kept taking acid suppressants during the study period; and (2) the infant group accounted for up to 39.2% of the recruited study group, and infants have more nonacid reflux. The relation between reflux symptoms, endoscopic or histologic findings, and exposure of the esophagus to acid is considered to be complex.13 Previous studies tried and failed to correlate endoscopic findings with clinical symptoms reliably.14 The correlation between MII-pH parameters and endoscopic findings remains an issue.15 Now we know that the fundamental abnormality in GERD is exposure of the esophageal epithelium to reflux content, resulting in tissue injury and/or symptoms. Acid is the key element in reflux content in the production of esophagitis and/or microscopic alterations.16 According to previous studies in adults, macroscopic mucosal changes of the esophagus were more common in patients with increased acid exposure.17 However, few studies documented the correlation between endoscopic reflux esophagitis and MII-pH in pediatric patients.18 Different endoscopic grading systems applied in different ages may produce inconsistent results.19,20 Our pilot study determined the relationship between the parameters of MII-pH and the presence of endoscopic reflux esophagitis in the pediatric population. We further set up the cutoff value of DeMeester score 21, duration of longest acid reflux 17 minutes, and occurrence of acid reflux for more than 5 minutes of MII-pH variables to predict the presence of endoscopic reflux esophagitis. Different treatment strategies are suggested based on the severity of reflux esophagitis. In our study, ROC analysis yielded the optimal cutoff value of 3 episodes per day of acid reflux for more than 5 minutes to discriminate severe from mild reflux esophagitis. According to these parameters, we could apply this noninvasive method to establish useful predictors for esophagitis other than endoscopy. For the confirmation of mucosal lesions, endoscope is the diagnostic mode of choice. MII-pH parameters are potentially a novel marker for esophageal mucosal integrity.15 Therefore, the combination of MII-pH and endoscopy may achieve a better diagnostic accuracy. The possible problem of this MII-pH method is lack of normal values for all of the age groups.21,22 We made a subgroup analysis according to different ages, individual grading of reflux esophagitis, and underlying disease variables. However, these results showed no statistically significant power for comparison due to unevenly distributed case numbers in our study. The numbers of patients with different grading of endoscopic reflux esophagitis in our study were not evenly distributed due to the small sample size, which rendered us unable to exclude selection bias. This drawback could be solved if more patients are enrolled in further studies. In conclusion, our study demonstrated that MII-pH monitoring added significantly to our understanding of GER and its complications. We also illustrated the parameters of MII-pH to predict the presence of endoscopically-
Please cite this article in press as: Liu Y-W, et al., The Correlation between Endoscopic Reflux Esophagitis and Combined Multichannel Intraluminal Impedance-pH Monitoring in Children, Pediatrics and Neonatology (2016), http://dx.doi.org/10.1016/j.pedneo.2015.09.008
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Intraluminal Impedance-pH Monitoring in Children proven reflux esophagitis in children. MII-pH was also a less invasive procedure than EGD because the procedure does not need intravenous sedation and has no radiation exposure. For the detection of mucosal lesion, EGD is still indicated for the complementary purpose of 24-hour MII-pH study.
5
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Conflicts of interest The authors have no potential, perceived, or real conflict of interest.
Acknowledgments
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This work was supported by a grant from National Taiwan University Hospital (NTUH.100-M1671).
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