Gastro-esophageal reflux disease (GERD) in otherwise healthy older children and adolescents is a significant source of morbidity [1-3]. There have been only a few studies for the prevalence of GERD in Korean pediatric population [4-6]. Older children and adolescent spend extended hours of sitting at desk at school and home while cramming with their subjects. Thus, these children seem to develop obesity or adult-like GERD symptoms. Even though the pediatric GERD symptoms are considerably different from those in adults, a global consensus is that neurologically intact older children and adolescents can be diagnosed and initiated with the similar treatments used for typical adults' reflux symptoms like heartburn and regurgitation [7,8]. Meanwhile, children have been reported to have more of epigastric pain and regurgitation including extra-esophageal symptom (ex: cough) [4-6,9]. These GERD symptoms interfere with daily activities in about 30% of pediatric patients [4]. Both non-erosive reflux disease (NERD) and erosive esophagitis (EE) present very similar symptoms that pediatric GERD diagnosis can be challenging in the absence of multiple diagnostic studies like endoscopy, esophageal pH monitoring, and/or esophageal multi-luminal impedance measurement (pH-MII) in primary pediatric clinics. The prognosis of GERD in healthy children is positive after treatment [10]. The children with risk factors, especially hiatal hernia, asthma, or a strong family history of GERD may develop a recurrent and chronic GERD later in their life [11-15]. Therefore, an early detection and proper treatment of GERD in those at-risk children lead to fewer complications, possibly preventing a development of subsequent adult GERD. As for treatment, proton pump inhibitors (PPIs) have been known to be efficacious and safe for pediatric GERD. Recently, PPIs and antacid have been overly used up to several folds higher than before in children with GERD. Unfortunately there has also been an increase of children treated with acid suppressants who developed adverse events related to drugs (ex: community-acquired pneumonia or gastroenteritis) [16]. Thus, it is imperative that pediatricians should have a better understanding of pediatric GERD and be cognizant of the side-effects of the medications. In this paper, GERD was reviewed with subtypes of EE/NERDs and treatments' issues in otherwise healthy older children and adolescents.

The prevalence of GERD in children varies according to age and country. In USA, 5-8.2% in children in ages of 10 to 17 years was diagnosed with weekly GERD symptoms [3]. 12.4% in children performed endoscopy was diagnosed with EE [11]. While in UK, 10.9/1,000 persons per year for the period of 2000 and 2005 have reported to have a newly diagnosed reflux esophagitis [15]. In adult studies, the prevalence of GERD (ex: weekly heartburn or acid regurgitation) in Asia has been known to be less (5%) than Western countries (20%). Meanwhile, Korean adult patients with erosive reflux esophagitis visiting a secondary or tertiary hospital were reported to have its prevalence rate of 11.8% [17]. In Korean children with upper abdominal pain, EE was reported to be 5.7% in 1992 [5] and 19.9% in 2008, respectively [6]. Other GERD children's complaints were mostly epigastric pain and regurgitation (over 60%). Heartburn was reported to be 18.6% in EE children and 2.9% in NERD children [4]. The frequency of EE seemed to be similar to that of NERD in GERD children [9,18].

About 39-42% of GERD children and adolescents (ages of 6 to 17 years) had either a history of gastro-esophageal reflux (GER) in infancy and/or a strong family history of GER [13]. Generally speaking, childhood GERD often continues to develop into adulthood GERD, indicating that this is a life-long disease which may even turn into Barret's esophagus, ulcer, and/or stricture [19].

GER is a physiologic result of the transient relaxation of the lower esophageal sphincter (TLESR) which is often triggered by gastric distension after meal, nasogastric tube, right lateral position, small volumes of liquid meal, etc. When the esophageal protective mechanism is altered, then pathologic GER will show troublesome symptoms during TLESRs, which can be manifested in different reflux types. It has not been clear what underlying mechanism causes which GERD type [12,18,20,21]. GERD ranges from NERD to severe EE depending on the pH value: severe GERD has a higher acid level (pH<4) and liquid reflux, while NERD has nonacid (pH>7), weak acid level (4<pH<7), bile, or gas in refluxate which enhances their perception of reflux. There is no significant difference in acid secretory capacity but pathologic esophageal acid exposure and sensitivity to acid exposure is different between EE and NERD [20]. Mixed reflux with acid and bile is the predominant form in children with reflux esophagitis but the rates of pathological acid reflux in EE is significantly higher than that of NERD [18,22,23]. The other following factors are also considered for GERD: delayed gastric emptying, decreased esophageal clearance, hypotonic lower esophageal sphincter, visceral neural pathway dysfunction, sustained esophageal contraction, and/or abnormal tissue resistance [15,24]. One of the risk factor is a hiatal hernia which comes with a greater TLESRs frequency depending on its size [21]. This hiatal hernia occurred in 17-39% of children with GERD who had required a long-term treatment [11,12,25]. Its incidence was higher in EE (7.7%) than in NERD (2.5%). Timing of each TLESR was important as the reflux occurred throughout the postprandial period in GERD adults with large hiatal hernia in recumbent (right lateral) or sitting posture [21]. In patients with small hiatal hernia and healthy volunteers, most acidic TLESRs occurred during the first postprandial hour [21]. Acid pocket (pH 1.6) of unbuffered gastric juice area extending 2 cm below the lower esophageal sphincter might have been a postulated factor in adult GERD patients with a hiatal hernia. But acid pocket of hiatal hernia could not answer clearly about acidic reflux in GERD adults and it also needs to be proven in GERD children [20,21].

Nonacid reflux occurs significantly during meal and postprandial period (within 2 hours) in GERD children. Nonacid reflux decrease to the one-third level from initial reflux, but acidic reflux decrease to the two-third level of initial reflux beyond postprandial (after<2 hours) in GERD children [23].

In children and adolescents, their lifestyles associated with heartburn have to be addressed. Korean children with GERD had their diet related to overeating, eating late at night, drinking soda, eating salty, spicy, or greasy foods, though they were rated not to be obese [4]. A history of small for gestational age or preterm may been linked to an esophageal adenocarcinoma later [26]. Other factors include history of chronic respiratory disorder such as child or teen-aged wheezer or adolescent onset asthma [14,27]. Moderate obese (16%) and extreme obese children (32%) are likely to have more GERD comparing to normal weight children [12].

Though there is no golden standard for the GERD test battery yet, a combination of tests is generally required in order to properly diagnose GERD. The initial stage assessment should involve a thorough history taking with a physical examination, and an empirical trial (2 weeks) of PPI or histamine-2 receptor antagonist (H2RA). This initial assessment and treatment trial would be sufficient for children with typical symptoms of GERD like regurgitation or heartburn [8,28]. However, GERD in children manifests differently from that in adults. The GERD in children often accompany regurgitation, vomiting, abdominal pain, or cough and the prevalence and severity of those symptoms are very similar between EE and NERD children. Heartburn specific for GERD (2.7-58%) was less in children and adolescents than that in adults, but it was higher in EE children (18.9%) than in NERD (2.9%) [4,6,9]. Thus, clinicians would have a difficult time to objectively assess the severity of esophagitis based on presenting symptoms.

An empirical trial of acid suppressants as a diagnostic test/treatment has been clinically useful in GERD children in the absence of any alarming signs such as failure to thrive or dysphagia [7,8]. A 2-week course of acid suppression with PPIs or H2RAs has not been proven conclusive though.

If their symptoms persist, then an endoscopy should be considered especially for the cases of suspected esophagitis. Endoscopy has proven to be a valuable procedure in children with a persistent symptom like a suspected esophagitis. This procedure has low sensitivity (41%) and specificity (77%) as for the diagnostic tool of GERD [6]. The endoscopic findings of EE show mostly mild grade lesions with patchy distribution according to the Los Angeles Classification: 52% of GERD children (ages of 12-17) showed grade A esophageal lesions of EE (mucosal break≤5 mm) and 39% of them showed grade B (mucosal break≥5 mm) [9,25]. For NERD, the endoscopic results show either normal condition or minimal changes, grade M (e.g., erythema and/or whitish turbidity) but histological changes were compatible to GERD [25]. There were no defined histological distinction between EE and NERD. The dilation of intercellular spaces (DIS) could be an important histological marker of EE in children as DIS occurs even after a brief exposure of the esophageal mucosa to a small amount of bile acids. DIS can revert to normal after the resolution of heartburn with PPI [25]. EE and NERD are spectrums of GERD in children.

The goal of acute therapy is to have a complete relief of any painful symptoms, to enjoy an improved quality of life, and to resolve possible esophagitis. For a long-term therapy, its goal is to achieve a complete relief of the symptoms and to heal esophagitis with a minimal dose medication within a short time frame. Undoubtedly, any recommendations should be tailored for each patient with GERD [29]. The efficacy of a therapy is monitored by the degree of symptom relief without a routine endoscopic follow-up. Endoscopic monitoring is needed in cases of atypical or persistent symptoms or signs after an adequate recommended therapy, higher grade EE, or esophageal stricture at presentation.

When given adequate doses, PPIs can safely work to relieve GERD symptoms and heal esophagitis in children. The level of this initial treatment success would then impact its long-term outcome for reflux symptoms and esophagitis. There have been inconsistent findings on long term outcomes. A study showed that a majority of treated GERD children did not have a recurrence [10], while another study showed that 30% of adults were taking either H2RAs or PPIs approximately after a 15-year duration of follow-up of GERD diagnosed at a mean age of 5 years [43]. 7% of treated esophagitis have shown recurrence after 9 month [19]. It appeared that GERD in infancy and childhood might be correlated with a reflux disease later in life [43]. Particularly EE in children is now believed to develop into a chronic disease [44].

The definition of GERD treatment failure is controversial but it means incomplete or unsatisfactory symptoms in response to a full course of PPIs [38]. Intragastric pH<2.0 may be a predictor of non-healing. Most GERDs including grade M, A or B, have improved well after a PPI treatment over 4 to 8 weeks, but a considerable number of EE of grade C or D have failed to respond to the treatment. Because of these unsatisfactory outcomes of the GERD treatments, the more flexible dosing in relation to meals and lifestyle should be considered. One of the undeniable factors of these negative outcomes is that patients often do not adhere to the rigorous regimen of prescribed treatment which includes resolute changes of diet and lifestyle. The reasons for a treatment failure have known to be multifactorial [38].

A management of PPIs treatment failure involves multiple steps: 1) stopping of PPIs for 1 week, 2) re-endoscopy, 3) esophageal pH monitoring, or pH-MII, etc. Esophageal pH monitoring can be useful when evaluating the efficacy of antisecretory therapy or to correlate symptoms (ex: cough, chest pain) with acid reflux episodes, to select children with wheezing or respiratory symptoms in whom GER becomes an aggravating factor, and to evaluate the success of pre- and post antireflux surgery. A weakness of esophageal pH monitoring is that it does not have an absolute clinical value due to its limitations of not being able to detect nonacid reflux 2 hours postprandial when GER occurs.

pH-MII can be used to detect acid-, weak acid-, and nonacid-reflux episodes. A significant number of GERs include non-acidic reflux [18,23]. Nonacid-, gas-GER is associated with a respiratory disorder like asthma [45,46]. This method is superior in terms of finding the temporal relationship between the symptoms and GER, when evaluating esophageal bolus transport or, probing the proximal extent of GER episodes. For these with treatment failures, children need to be referred to a pediatric gastroenterologist.

There has been an alarming increase of otherwise healthy older children and adolescents presented with gastro-esophageal reflux symptoms in community pediatric clinics. The GERD usually responds well with H2RA and PPI treatments, but in some cases these treatments have been linked to adverse events of pneumonia or gastroenteritis. Therefore, it is imperative that pediatricians should develop an in-depth understanding of the GERD mechanism, an effective dosage and treatment duration of a specific medication, and its side effects of short term/long-term usage in order to optimally address each patient and to achieve desired therapeutic goals.