Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents

INTRODUCTION — Gastroesophageal reflux disease (GERD) is present when passage of gastric contents into the esophagus causes troublesome symptoms or complications [1]. The range of symptoms and complications of GERD in children varies with age.

This topic review focuses on the clinical manifestations and diagnosis of GERD in children and adolescents. Other topic reviews relevant to GER and GERD in the pediatric age group are:

●(See "Management of gastroesophageal reflux disease in children and adolescents".)

●(See "Gastroesophageal reflux in infants".)

●(See "Gastroesophageal reflux in premature infants".)

DEFINITIONS

●Gastroesophageal reflux – Gastroesophageal reflux (GER) refers to the retrograde passage of gastric contents into the esophagus, with or without regurgitation and/or vomiting [2]. This is a normal physiologic process that occurs in healthy infants, children, and adults. Most episodes are brief and do not cause symptoms, esophageal injury, or other complications.

●Gastroesophageal reflux disease – Gastroesophageal reflux disease (GERD) is present when reflux episodes are associated with complications or troublesome symptoms [1,3].

●Regurgitation versus vomiting – The term "regurgitate" describes reflux to the oropharynx, and "vomit" describes expulsion of the refluxate out of the mouth but not necessarily repetitively or with force. The terms are often used interchangeably in clinical practice. In this review, we will use the term "regurgitate" to describe obvious GER into the mouth, whether or not the refluxate is expelled from the mouth. Recurrent regurgitation and vomiting are often caused by GER but occasionally are caused by more serious problems, including underlying anatomic, metabolic, or neurologic abnormalities, which should be considered when indicated by the patient's clinical presentation (table 1). (See 'Recurrent vomiting or regurgitation' below.)

●Rumination – The term "rumination" describes a distinct phenomenon in which food is voluntarily regurgitated into the mouth, masticated, and then re-swallowed. This disorder should be considered as a possible cause of GER, but it has a behavioral etiology and specific treatment. (See 'Recurrent vomiting or regurgitation' below and "Rumination syndrome".)

EPIDEMIOLOGY AND NATURAL HISTORY — Few large population-based studies have described the epidemiology of GERD in children. Most studies focus on the prevalence of GERD in specific groups. Comparison among studies is also limited by the use of different definitions of GERD and the variable extent to which other possible causes of symptoms that were attributed to GERD were investigated.

●Prevalence – According to a large community-based study of children in the United States, the prevalence of various symptoms suggestive of GER was 1.8 to 8.2 percent [4]. Among adolescents, 3 to 5 percent complained of heartburn or epigastric pain and 1 to 2 percent used antacids or acid-suppressing medication. The prevalence of GERD in adults in the Western world is approximately 10 to 20 percent [5]. Contrary to previously held beliefs, GERD does not appear to be limited to Western countries. The prevalence of GERD in children appears to be rising worldwide, although it is unclear whether the rise reflects increasing case identification or increases in obesity or other conditions that promote GERD [6].

Higher rates of GERD are seen among children with a history of prematurity, pulmonary diseases, and developmental and neuromuscular disorders such as cerebral palsy and muscular dystrophy [7-9]. Children with Down syndrome are also at increased risk for GERD and other esophageal motor abnormalities for reasons that are poorly understood [10,11]. These groups of children also appear to be at increased risk for developing respiratory complications related to GERD and represent a significant proportion of children referred for antireflux surgery. GERD also appears to be relatively common in children with obesity or cystic fibrosis [6,12]. GERD is more common in individuals with cystic fibrosis because the chronic cough induces reflux and the buffering capacity of the saliva is impaired, resulting in prolonged acid exposure in the distal esophagus. (See "Cystic fibrosis: Overview of gastrointestinal disease".)

●Complications – Respiratory complications (recurrent pneumonia and bronchiectasis) are most common in individuals with a history of prematurity, pulmonary diseases, developmental and neuromuscular disorders, and Down syndrome. Other complications of prolonged GERD include distal esophageal stricture, Barrett esophagus, and esophageal adenocarcinoma, which are more common in individuals with esophageal dysmotility secondary to repair of esophageal atresia in the perinatal period compared with individuals without this congenital defect [13,14]. Anxiety, depression, and sleep disturbance are increased in patients with heartburn [15].

●Natural history – Regurgitation in infants is common and typically decreases or resolves during the first year of life (see "Gastroesophageal reflux in infants"). Although the problem usually resolves by the end of infancy, there is a weak association with GERD later in life. As an example, frequent regurgitation during infancy or a history of GERD in the mother (but not the father) predicts the risk of reflux-related symptoms during childhood. This was demonstrated in a prospective cohort study in which children who had more than 90 days of frequent regurgitation during the first two years of life were more likely to have heartburn around nine years of age [16].

Symptoms of GERD during childhood may persist into adolescence and adulthood ("tracking"). In a survey of 207 patients who were diagnosed with GERD based on an endoscopic examination showing esophagitis in childhood (mean age five years), approximately one-third had symptoms of significant GERD during early adulthood (approximately 15 years later) [17]. At least 9 (up to 23) percent had weekly symptoms of GER. Among those responding to the survey, 30 percent were currently taking acid-suppressing medications and 24 percent had undergone fundoplication. Other studies have shown similar results, but the lack of prospective trials limits the reliability of these observations [18].

●Unanswered questions – Several questions related to the epidemiology and natural history of GERD in children remain unanswered or only partly understood:

•Relationship between GER and respiratory diseases (chronic cough, asthma, and pneumonia).

•Relationship between childhood GERD and GERD-related complications in adulthood.

•Health care burden related to the diagnosis and treatment of childhood GERD.

•Impact of GERD on quality of life for affected children and their families.

•Mechanisms underlying the observed association between GERD and overweight/obesity – A common explanation is that obesity causes GERD via increased intraabdominal pressure, based primarily on adult data (see "Pathophysiology of reflux esophagitis", section on 'Obesity'). Another possibility is that the association may be mediated by dietary factors, as suggested by a report that children and adolescents with GERD consume more energy and fat compared with controls matched by body mass index, and that GERD severity (erosive esophagitis versus nonerosive GERD) is associated with consumption of increased protein and fat (but lower polyunsaturated fats) [19,20].

CLINICAL MANIFESTATIONS — The most common symptoms of GER and GERD vary according to age, although overlap may exist.

●Infants – GER is common in infants and usually is not pathologic. Regurgitation is present in 50 to 70 percent of all infants, peaks at age four to six months, and typically resolves by one year. A small minority of infants with GER develop other symptoms suggestive of GERD, including irritability, feeding refusal, hematemesis, anemia, respiratory symptoms, and failure to thrive. The clinical manifestations and management of GER in this age group are discussed separately. (See "Gastroesophageal reflux in infants".)

●Preschool-aged children – Preschool-age children with GERD may present with intermittent regurgitation. Less commonly, they may have respiratory complications including persistent wheezing. Decreased food intake, poor weight gain, or food aversion without any other complaints may be a symptom in young children. All of these symptoms are nonspecific and insufficient to make a definitive diagnosis of GERD.

A more specific symptom of GERD is Sandifer syndrome, an unusual intermittent posturing consisting of arching of the back, torsion of the neck (towards either side), and lifting up of the chin [1,21]. Sandifer syndrome sometimes occurs in typically developing preschool-aged children, as well as those who are developmentally delayed, as in the original descriptions [22]. The symptom usually resolves with effective treatment of the GERD [21]. The differential diagnosis includes other causes of acquired torticollis in children. (See "Acquired torticollis in children".)

●School-aged children and adolescents – The cardinal symptoms of GERD in older children and adolescents are chronic heartburn and/or frequent regurgitation (either overt regurgitation or tasting stomach acid in the mouth) [23]. Some patients report epigastric pain, nausea, and/or dysphagia (difficulty swallowing). Nonspecific symptoms that may be present include halitosis, excessive belching, wheezing, or erosion of dental enamel (especially on the inner surfaces of the teeth) [1,24,25]. Many younger children will not localize pain and report diffuse abdominal discomfort.

In older children, GERD-related chest pain often has the following characteristics:

•Occurs after meals

•Awakens patients from sleep

•Is described as burning or squeezing and is located substernally and sometimes radiates to the back

•Lasts minutes to hours and resolves either spontaneously or with antacids

•May be exacerbated by emotional stress

Complications of GERD, including esophagitis, strictures, Barrett esophagus, and hoarseness due to reflux-induced laryngitis, also may be seen. (See "Barrett's esophagus: Epidemiology, clinical manifestations, and diagnosis" and "Approach to chronic cough in children".)

Extraesophageal disorders that are associated with GERD also may be seen in older children and adolescents. In a large case-control study of children without neurologic defects, GERD was an independent risk factor for developing sinusitis (adjusted odds ratio [OR] 2.3), laryngitis (OR 2.6), asthma (OR 1.9), pneumonia (OR 2.3), and bronchiectasis (OR 2.3) (see 'Asthma' below and 'Recurrent pneumonia' below) [26]. GER is also associated with otitis media with effusion, but causality has not been established. (See "Otitis media with effusion (serous otitis media) in children: Clinical features and diagnosis", section on 'Pathogenesis'.)

●Nonverbal children – Young or nonverbal children may communicate their GERD-related chest pain by tapping their chest or showing general irritability or distress. GERD is common in children with autism and may be manifested only by unexplained or self-injurious behaviors.

DIAGNOSTIC APPROACH — The diagnostic process outlined below is generally consistent with an official consensus statement and systematic review issued by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition/European Society for Paediatric Gastroenterology, Hepatology and Nutrition [1] and the American Academy of Pediatrics [3].

History — The differential diagnosis of GERD in children is broad, particularly when the principal complaint is regurgitation, vomiting, or abdominal pain (table 1). The diagnostic possibilities can be narrowed based upon the age of the child and the pattern of symptoms, using a thorough medical history (table 2) (see "Approach to the infant or child with nausea and vomiting"). The history should include the following elements:

●Presence of heartburn/chest pain or abdominal pain, regurgitation or vomiting, water brash, and whether there is associated nausea

●Onset of symptoms and relation to meals

●Dysphagia (difficulty swallowing) or odynophagia (pain while swallowing)

●Underlying disorders including neurologic dysfunction or congenital anomalies

●Asthma, pneumonia, or chronic cough

●Food aversion

●Food allergies

●Functional constipation

●Growth assessment

●Medication history

Functional constipation may be associated with dyspeptic symptoms including GER, heartburn, and nausea [27,28]. In many individuals, constipation may be unrecognized as the dyspeptic symptoms are the presenting complaint [27]. The suspected mechanism is most likely that constipation delays gastric emptying via an intraintestinal reflex, termed the "cologastric brake" [28]. The possibility of underlying constipation is suggested by palpation of stool distending the sigmoid colon and/or a digital rectal examination that detects hard stool in the rectal vault. Effective treatment of the underlying constipation may relieve the dyspeptic symptoms and avoid invasive procedures or unnecessary long-term pharmacotherapy for presumed GERD. (See "Constipation in infants and children: Evaluation".)

Suggested approach for common clinical scenarios — The previous discussion underscores the variable presentation of GERD in infants and children and the need to modify the diagnostic approach based upon the patient's age, type of symptoms, and symptom severity. The following sections will provide general recommendations for diagnosis in infants and children with commonly seen clinical presentations. These recommendations are consistent with the guideline issued by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition [1].

Recurrent vomiting or regurgitation — Otherwise healthy children with recurrent vomiting or regurgitation after reaching the age of 18 months usually require evaluation. The differential diagnosis of regurgitation and vomiting is broad and depends on the age group and associated symptoms (table 1). For otherwise healthy children and adolescents with recurrent regurgitation or vomiting and no other symptoms, a thorough history and physical examination is often sufficient to exclude diagnoses other than GER.

Warning signs that suggest a diagnosis other than GERD include:

●Fever

●Weight loss or faltering growth

●Abdominal tenderness or distension

●Bilious vomiting

●Marked hematemesis

●Hepatosplenomegaly

●Headache or new neurologic symptoms

●Other systemic symptoms

Patients with any of these features warrant additional steps in the evaluation. (See "Approach to the infant or child with nausea and vomiting".)

The differential diagnosis of GERD includes several disorders that should be explored by the history (table 1):

●Gastroparesis – Gastroparesis is the condition of impaired gastric emptying. This may cause postprandial vomiting, which usually occurs several hours after eating. Viral-induced gastroparesis may begin acutely after an episode of gastroenteritis and persist for several weeks or months thereafter and, occasionally, as long as 18 months. (See "Approach to the infant or child with nausea and vomiting", section on 'Gastroparesis'.)

●Rumination or psychogenic vomiting – Rumination syndrome is a psychogenic disorder in which the individual voluntarily regurgitates and re-swallows food, apparently as a self-comforting or habitual measure. The repeated episodes usually occur immediately after a meal. Rumination is more common among individuals with developmental disabilities but also occurs among typically developing children, adolescents, and adults. The disorder may be initially triggered by an episode of gastroenteritis, GERD, or by body weight concerns as a form of bulimia [29]. Distinguishing rumination from GERD may be difficult and requires a high index of suspicion. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis" and "Approach to the infant or child with nausea and vomiting", section on 'Bulimia' and "Approach to the infant or child with nausea and vomiting", section on 'Rumination syndrome'.)

●Pregnancy – For postmenarchal girls with vomiting, the clinician should explore the possibility of pregnancy, with testing if indicated.

●Cannabis hyperemesis – For adolescents, the clinician should specifically ask about cannabis use. (See "Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects", section on 'Medical and systemic effects'.)

Additional evaluation is appropriate if the history does not suggest the above disorders or if the GER symptoms are frequent, cyclical, or persistent and cause distress. In this case, the evaluation usually should include an upper gastrointestinal series to look for anatomic abnormalities. An upper endoscopy with biopsy may be helpful in determining if the child has esophagitis (either peptic or eosinophilic esophagitis [EoE]). In older children or adolescents with heartburn or other symptoms suggestive of GERD, a four- to eight-week trial of acid suppression may be used as a diagnostic test for peptic disease as an alternative to an initial endoscopy [1]. (See 'Available diagnostic techniques' below.)

Heartburn — Children or adolescents with heartburn can be treated empirically with lifestyle changes (eg, dietary modification, positioning, avoiding alcohol and nicotine, and weight management if appropriate) and an empiric trial of acid-suppressing medication (eg, proton pump inhibitor [PPI]) for four to eight weeks [1]. A clear and complete response to acid suppression supports the diagnosis of GERD. Persistent or recurrent symptoms should prompt a referral for an upper endoscopy with biopsy, especially if any dysphagia is present. (See "Management of gastroesophageal reflux disease in children and adolescents", section on 'Heartburn'.)

Dysphagia or odynophagia — Patients with dysphagia (difficulty swallowing) or odynophagia (pain with swallowing) usually should undergo specific evaluation.

Patients with dysphagia typically complain of difficulty initiating a swallow or the sensation of solids or liquids getting stuck in the esophagus [23]. Dysphagia for solids is most commonly caused by esophageal inflammation related to GERD, EoE, or an esophageal stricture [30]. These patients should be evaluated by an esophageal contrast study and/or upper endoscopy with biopsies.

Dysphagia for liquids as well as solids raises the possibility of a motility disorder such as achalasia. The first step in the evaluation for achalasia is a radiograph of the chest, looking for a lack of air in the stomach and an intraesophageal air-fluid level. A barium esophagram is beneficial to look for esophageal distension and the classic "bird beak" appearance as well as the possibility of a stricture. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)" and "Achalasia: Pathogenesis, clinical manifestations, and diagnosis".)

A common cause of sudden-onset odynophagia (pain with swallowing) in adolescents is pill esophagitis. This is caused by direct mucosal injury by certain drugs including tetracyclines (doxycycline and minocycline) that are commonly used for treatment of acne or by antiinflammatory agents including aspirin. Pill esophagitis is more likely in patients if the pill is swallowed either with little or no liquid and/or just before lying down. If the symptoms are mild, then empiric treatment with sucralfate or a PPI is reasonable. If the symptoms are severe or progressive, performing an upper endoscopy prior to initiating treatment is important to exclude infectious causes of esophagitis that cause odynophagia, including Candida, cytomegalovirus, and herpes. (See "Pill esophagitis".)

Uncommon causes of dysphagia that may present in children or adolescents include motility disorders (eg, myotonia) and systemic sclerosis (scleroderma) (table 3). (See "Approach to the evaluation of dysphagia in adults", section on 'Symptom-based differential diagnosis'.)

Asthma — GER may be a trigger for asthma in some patients. Abnormal reflux, as measured by symptoms or by esophageal pH monitoring, occurs in 25 to 75 percent of children with persistent asthma, and the association increases with severity of either condition; however, whether or not this association is causal remains unclear [31,32]. Many studies have shown clinical improvement in asthma when patients are treated for GER [31,33]; however, pinpointing patients who are likely to respond to treatment remains problematic [1,34].

For patients with asthma and symptoms that strongly suggest GERD (including heartburn in older children and adolescents or chronic regurgitation or vomiting in infants and younger children), we suggest a three-month trial of acid suppression. (See "Management of gastroesophageal reflux disease in children and adolescents", section on 'Asthma with gastroesophageal reflux'.)

GER may trigger asthma in some patients even in the absence of symptoms of GERD. Therefore, some experts recommend esophageal pH and multichannel intraluminal impedance (pH-MII) monitoring or an empiric three-month trial of vigorous acid suppression for patients with either of the following characteristics, particularly if they lack seasonal or allergic symptoms [31]:

●Nocturnal asthma more than once a week

●Continuous requirement for oral corticosteroids, high-dose inhaled corticosteroids, more than two courses of oral corticosteroids per year, or persistent asthma that does not allow the patient to be weaned from medical management

Similar approaches are used for adult patients with asthma and possible GERD. (See "Gastroesophageal reflux and asthma".)

Recurrent pneumonia — GERD can be associated with recurrent pneumonia, especially in patients with underlying neurologic dysfunction, or with anatomical abnormalities that predispose to aspiration, such as cleft lip/palate, choanal atresia, or micrognathia. Such patients should be evaluated for swallowing dysfunction using videofluoroscopy and/or fiberoptic endoscopic evaluation of swallowing. Esophageal pH monitoring has low sensitivity and specificity in detecting whether aspiration pneumonia is related to reflux in an individual patient but may help establish the diagnosis in selected patients with suspected aspiration when combined with other investigations. (See "Aspiration due to swallowing dysfunction in children".)

Other than direct evaluation of swallowing for patients with suspected swallowing dysfunction, no techniques are available to determine definitively whether GERD is causing chronic aspiration in an individual patient. Measurement of lipid-laden macrophages (obtained by bronchoalveolar lavage) and nuclear scintigraphy have been used for this purpose, but neither technique can reliably determine whether a patient has chronic aspiration [1]. (See 'Other tests' below.)

Patients with recurrent pneumonia should also be evaluated to exclude underlying causes other than GERD, including foreign body aspiration, cystic fibrosis, or immunodeficiency. A history of choking is highly suggestive of foreign body aspiration, even if the choking occurred days or weeks prior to the onset of respiratory symptoms. An H-type tracheoesophageal fistula should also be considered in a child with recurrent pneumonia, especially if the same segment of the lung is always involved. (See "Airway foreign bodies in children".)

Chronic cough — Most authorities suggest that GERD is not a common cause of isolated chronic cough in children, except in those with neurologic abnormalities predisposing to aspiration, as described above. Children with chronic cough should be evaluated for a variety of underlying causes, including asthma. A chronic "wet" cough typically has an underlying cause other than GERD, including foreign body aspiration or protracted bacterial bronchitis. (See "Approach to chronic cough in children" and "Causes of chronic cough in children", section on 'Overview of causes in children'.)

Other conditions — Stridor, hoarseness, sinusitis, and otitis media have been associated with GERD, mostly in case reports and case series in children. Neither the association with GER nor response to antisecretory therapy have been established by controlled studies [1]. Therefore, other potential etiologies should be investigated in patients with these symptoms or signs. (See "Otitis media with effusion (serous otitis media) in children: Clinical features and diagnosis", section on 'Pathogenesis' and "Common causes of hoarseness in children", section on 'Gastroesophageal reflux/laryngopharyngeal reflux'.)

Similarly, GER is not a trigger for most infants with apnea or for those who have experienced a brief resolved unexplained event (BRUE). In the few cases in which GER is strongly suspected with recurrent apnea, combined pH-MII monitoring and polysomnographic recording with symptom diary may help establish cause and effect. (See 'Esophageal pH monitoring or impedance monitoring' below and "Acute events in infancy including brief resolved unexplained event (BRUE)", section on 'Gastroesophageal reflux or swallowing dysfunction'.)

AVAILABLE DIAGNOSTIC TECHNIQUES — The following sections summarize characteristics of the tests that are used to evaluate individuals with symptoms of GER or GERD. The clinical approach to selecting among these tests depends on the patient's presenting characteristics. (See 'Suggested approach for common clinical scenarios' above.)

Empiric treatment — An empiric trial of acid suppression is often used as a diagnostic test and is suggested for older children and adolescents with uncomplicated heartburn [1]. The trial typically consists of a four- to eight-week course of acid-suppressing medication (eg, a proton pump inhibitor [PPI] or histamine type 2 receptor antagonist). An empiric trial of a PPI may not be a valuable diagnostic test in infants and young children, in whom symptoms of GERD are less specific; however, response after a two-week trial of a PPI has been used as inclusion criteria for clinical trials in infants with GER [35]. Studies in adults suggest that empiric treatment is a cost-effective approach in selected patients, although the applicability of these results to children is uncertain [36]. (See 'Heartburn' above and "Medical management of gastroesophageal reflux disease in adults".)

Contrast radiography — Contrast studies of the esophagus are not indicated for most patients with suspected GERD, as they have low sensitivity and specificity [1,3,37] for diagnosing GERD when compared with esophageal pH or impedance monitoring [38,39].

However, contrast radiography may be useful for:

●Young infants with intractable reflux – To identify congenital abnormalities such as an antral web, pyloric stenosis, annular pancreas, duodenal web, or malrotation [40].

●Atypical presenting features, such as dysphagia or odynophagia – To identify anatomic abnormalities, such as hiatal hernia, Schatzki ring, achalasia, or strictures associated with acid or eosinophilic esophagitis (EoE). (See 'Dysphagia or odynophagia' above.)

●Suspicion of obstruction – To evaluate for intestinal malrotation with intermittent volvulus. Presenting features may include intermittent vomiting (particularly if bilious) with abdominal pain and distension.

Endoscopy and histology — Endoscopic evaluation of the upper gastrointestinal tract is indicated for selected patients in whom esophagitis or gastritis is suspected. These include children or adolescents with heartburn, hematemesis, or epigastric abdominal pain that fails to respond to or relapses quickly after empiric treatment [1,37]. In addition, endoscopy may be valuable in the evaluation of patients with recurrent regurgitation, dysphagia, or odynophagia; a history of food impaction; or in children with frequent GER that persisted from infancy until after two years of age.

At endoscopy, the examiner inspects the visual appearance of the esophageal mucosa, assesses the anatomy, and takes a series of biopsies for histologic examination. The findings help to determine the presence of strictures, webs, or rings as well as the severity of esophagitis and its complications, such as peptic strictures or Barrett esophagus, and to exclude other disorders such as eosinophilic, peptic, or infectious esophagitis. The diagnostic yield of endoscopy in children with symptoms suggesting GERD is not well established. In one large series of children undergoing endoscopy due to GERD symptoms, 35 percent were found to have erosive esophagitis [41]. In another large series of children undergoing endoscopy for GER, only 13 percent had histologic evidence of esophagitis, whereas more than 50 percent of those undergoing endoscopy for dysphagia had gross and histologic abnormalities [42].

Endoscopy can be performed safely in infants, toddlers, and older children. Procedure-related complications of diagnostic endoscopy and biopsy are rare [43]. Complications requiring medical attention, including under- or oversedation, occur in approximately 5 percent of cases [44,45]. The most common complication is transient sore throat or hoarseness, which occurs in approximately 35 percent of patients [45].

The endoscopy should include biopsies of the esophageal mucosa to evaluate for esophagitis, even if the esophagus appears normal on visual inspection [1,3,46]. Histologic abnormalities consistent with GERD include increased numbers of intraepithelial eosinophils, thickening of the basal cell layer, and elongation of the epithelial papillae [35,47,48]. In young children with esophagitis, the findings of basal zone hyperplasia are uncommon and other histologic features, such as the presence of neutrophils and eosinophils, and dilated vascular channels in papillae of the lamina propria are more typically seen [35]. Patients with reflux-associated esophagitis should be treated with acid suppression, as discussed in a separate topic review. (See "Management of gastroesophageal reflux disease in children and adolescents", section on 'Esophagitis'.)

The histologic features described above are only moderately specific for GERD. In patients with markedly increased numbers of eosinophils in esophageal biopsies, the possibility of EoE should be considered. EoE is a chronic immune-mediated disorder characterized by markedly increased intraepithelial eosinophils in greater numbers than noted in GERD. Symptoms of EoE and the number of intraepithelial eosinophils may not respond to acid suppression. EoE is increasingly recognized in children and adults, and the symptoms and histologic findings overlap with those of GERD, such that in some cases, it can be difficult to clearly distinguish between the disorders [49,50]. The number and distribution of eosinophils can help distinguish GERD from EoE. In children with GERD, the eosinophilic inflammation tends to be mild (<15 eosinophils per high-power field) and limited to the distal esophagus, whereas in children with EoE, the inflammation tends to be more severe (>15 eosinophils per high-power field) and located in the mid- or proximal esophagus. In addition, many patients with EoE have a history of atopy or peripheral eosinophilia and are more likely to fail to respond to antireflux treatment. Diagnostic and treatment approaches to patients with suspected EoE are discussed in a separate topic review. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)".)

Esophageal pH monitoring or impedance monitoring — Esophageal pH and multichannel intraluminal impedance (pH-MII) monitoring permits the assessment of the frequency and duration of esophageal acid exposure and its relationship to symptoms by placing a small sensor in the esophagus. However, the results may not correlate consistently with symptom severity, although there is a correlation with the presence of esophagitis on endoscopy [1,48,51]. Therefore, pH-MII can correlate symptoms of GERD with acid or nonacid reflux, which helps to raise or lower suspicion of GERD. However, pH-MII is not a routine or definitive diagnostic test for GERD and is not useful in many clinical situations, especially in infants.

A guideline based on expert opinion suggests that pH-MII may be useful in the following types of patients [52]:

●Atypical symptoms with unclear association with reflux – The pH-MII test helps by determining the correlation between a patient's symptoms with acid and nonacid reflux events. In patients with normal endoscopy results but ongoing symptoms, the test may support the following diagnostic categories [53]:

•Nonerosive reflux disease - Abnormal degree of acid reflux, and symptoms improve with acid suppression.

•Hypersensitive esophagus - Normal degree of acid reflux, but reported symptoms correlate with reflux events and respond to acid suppression. If no response to acid suppression, consider rumination syndrome.

•Functional heartburn - Normal degree of acid reflux, and no correlation between symptoms and reflux events.

●Atypical asthma – Nocturnal asthma more than once a week or persistent asthma that is refractory to medical management. (See 'Asthma' above.)

●Suspected EoE – For children with suspected EoE, pH-MII may useful to help distinguish this condition from GERD. Both EoE and GERD are associated with increased eosinophils in the esophagus, and in some children, distinguishing between the disorders may be difficult. The diagnosis of EoE is based on clinical and pathologic features including dysphagia, food impaction (in adolescents), feeding refusal (in toddlers), and symptoms of GERD in association with eosinophilic inflammation of 15 or greater eosinophils per high-power field. Both GERD and EoE may respond to PPI therapy, and response to PPIs is no longer considered useful to distinguish between these conditions [54-57]. Having less than 15 eosinophils per high-power field in the distal esophagus favors a diagnosis of GERD, while a higher number of eosinophils in the esophagus or documentation of normal esophageal pH or pH-MII monitoring helps to support a diagnosis of EoE. (See "Clinical manifestations and diagnosis of eosinophilic esophagitis (EoE)".)

●Refractory esophagitis – To determine the efficacy of acid-suppressive treatment.

The guideline also stresses that interpretation of pH-MII results requires clinical correlation and should not be considered a single definitive test for the diagnosis of GERD in infants and children [52].

Other tests — The following tests have limited utility in the evaluation of children with GERD but are occasionally used for selected patients:

●Bronchoalveolar lavage – Bronchoscopy with bronchoalveolar lavage is occasionally used to assess for evidence of recurrent small-volume aspiration. If aspirates contain a high percentage of lipid-laden macrophages, aspiration is thought to be more likely. However, this technique has low sensitivity and specificity. Even with careful measurements, the technique is not generally useful, as there is considerable overlap in findings between patients with aspiration and normal controls [1,58]. (See "Aspiration due to swallowing dysfunction in children", section on 'Flexible bronchoscopy with lavage'.)

●Nuclear scintigraphy – Tests employing nuclear scintigraphy are designed to detect aspiration and/or delayed gastric emptying. However, due to low sensitivity and specificity, they have a limited role in the evaluation of GERD in children [1]. Small amounts of technetium-99m are either mixed with milk and given to the patient to drink (gastroesophageal scintigraphy, also known as a "milk scan") or placed on the tongue, where it binds to saliva (salivagram). Gamma camera images of the chest are taken at defined intervals to detect the distribution of the isotope in the stomach, esophagus, and lungs. Gastrointestinal scintigraphy (milk scan) can detect aspiration of refluxed material into the lungs, unlike esophageal pH monitoring or MII. However, its sensitivity and specificity are poor when compared with other clinical or radiographic measures of aspiration. As a result, this test has a limited role in the evaluation and management of GERD in children [1,3]. (See "Aspiration due to swallowing dysfunction in children", section on 'Scintigraphy'.)

In patients suspected to have gastroparesis, the same scintigraphic technique can be used to detect abnormalities in gastric emptying as a cause of the reflux or when surgical intervention (fundoplication) for GERD is contemplated. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Scintigraphic gastric emptying' and "Management of gastroesophageal reflux disease in children and adolescents", section on 'Fundoplication' and "Approach to the infant or child with nausea and vomiting", section on 'Gastroparesis'.)

In selected patients who experience recurrent aspiration, a salivagram may be helpful in determining whether the aspiration is caused by swallowing problems (antegrade aspiration) as opposed to GERD (retrograde aspiration) [59]. However, salivagrams appear to have low specificity due to frequent false-positive results, especially in infants and young children, and must be correlated with clinical evidence for aspiration. (See "Aspiration due to swallowing dysfunction in children", section on 'Scintigraphy'.)

●Esophageal manometry – Esophageal manometry is of minimal utility in the diagnosis of typical GERD [1]. Its main purpose is to diagnose a primary motor disorder such as achalasia in patients with suggestive findings on barium contrast radiography. In addition, some providers use esophageal manometry to evaluate peristaltic function before antireflux surgery. If significant esophageal dysmotility is detected, antireflux surgery should be approached with caution because it might exacerbate difficulties with swallowing food and/or saliva. (See "Surgical treatment of gastroesophageal reflux in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastroesophageal reflux in children" and "Society guideline links: Esophageal manometry and pH testing".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Acid reflux and GERD in children and teens (The Basics)" and "Patient education: Esophagitis (The Basics)")

●Beyond the Basics topics (see "Patient education: Gastroesophageal reflux disease in children and adolescents (Beyond the Basics)" and "Patient education: Acid reflux (gastroesophageal reflux) in babies (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definitions – Gastroesophageal reflux (GER) is common in infants, as manifested by regurgitation, and is generally not pathologic. The regurgitation usually resolves by 18 months of age. Gastroesophageal reflux disease (GERD) refers to GER that is associated with pathologic complications. (See 'Definitions' above and 'Epidemiology and natural history' above.)

●Clinical manifestations – Symptoms that suggest the possibility of GERD include (see 'Clinical manifestations' above):

•Recurrent regurgitation that continues after two years of age

•Refusal of food, especially solids

•Frequent complaints of heartburn

•Dysphagia (difficulty swallowing)

•Severe or progressive asthma that is not responsive to standard therapy for asthma

•Recurrent pneumonia, particularly in children with neurologic dysfunction

•Chronic hoarseness or stridor

●Differential diagnosis – The differential diagnosis of GERD in children is broad, particularly when the principal complaint is regurgitation, vomiting, or abdominal pain (table 1). The diagnostic possibilities can be narrowed based upon the age of the child, the pattern of symptoms, and a thorough medical history (table 2). (See 'History' above.)

Symptoms that are not typical for GERD include fever, asymptomatic vomiting, weight loss or faltering growth, abdominal tenderness or distension, bilious vomiting, marked hematemesis, hepatosplenomegaly, headache or new neurologic symptoms, or other systemic symptoms. GERD is occasionally associated with stridor, hoarseness, sinusitis, otitis media, or recurrent apnea, but, in most cases, these symptoms have other causes. Patients with these symptoms should be carefully evaluated for other disorders. (See 'Recurrent vomiting or regurgitation' above and 'Other conditions' above.)

●Evaluation – When children present with symptoms suggesting GERD, further work-up is appropriate. Selection of tests depends upon the clinical scenario (see 'Suggested approach for common clinical scenarios' above):

•Exclude constipation – For all patients, the evaluation should include assessment for the possibility of occult or associated constipation since constipation causes secondary reflux or dyspeptic symptoms in many children. (See 'History' above and "Constipation in infants and children: Evaluation".)

•Empiric trial of acid suppression – For patients presenting with mild or moderate symptoms of heartburn, initial time-limited empiric treatment with acid-suppressing drugs is reasonable. It may also be appropriate for selected patients with severe or refractory asthma, or those with frequent nocturnal asthma. (See 'Empiric treatment' above and 'Asthma' above and "Gastroesophageal reflux and asthma".)

•Endoscopy – Endoscopic evaluation of the upper gastrointestinal tract is indicated for patients with:

-Heartburn or epigastric abdominal pain that fails to respond to empiric acid suppression

-Dysphagia or odynophagia

-Selected patients who continue to have recurrent regurgitation after two years of age

The main goal is to identify esophagitis, which is usually caused by GERD and less often by eosinophilic esophagitis. (See 'Endoscopy and histology' above.)

•Esophageal pH and impedance monitoring – These studies may be useful for patients with atypical symptoms, atypical asthma, or suspected eosinophilic esophagitis, but generally not for a child with typical heartburn.

•Esophageal contrast radiography – This may be useful to exclude anatomic abnormalities in selected patients, such as those with dysphagia or odynophagia, young infants with intractable reflux, or those with suspected obstruction. It is not useful for other patients because it has low sensitivity and specificity for GERD. (See 'Contrast radiography' above and 'Dysphagia or odynophagia' above.)