Excessive regurgitation is one of the symptoms of GERD, but the terms regurgitation and GERD should not be used as synonyms [4]. While regurgitation (spilling, spitting up, posseting) is a typical GER symptom in infants, it is seldom in older children and adults. According to a recent review, about 25 % of infants present with regurgitation severe enough for parents to seek medical help, which can be limited to reassurance, e.g., by providing information on the natural evolution and adjusting feeding volume and frequency [1, 2, 18]. Regurgitation that persists after the age of 6 months strongly decreases during a 3-month follow-up with conservative treatment [19]. A prospective follow-up reports disappearance of regurgitation in all subjects before 12 months, although the prevalence of feeding refusal, duration of meals, parental feeding-related distress, and impaired quality of life was observed, was higher in those who presented with regurgitation (even after disappearance of symptoms) compared to those who never regurgitated [20].

Irritability or infant distress may accompany regurgitation and vomiting. However, in the absence of other warning symptoms, it is not an indication for extensive testing [1]. Parental coping-capacity or anxiousness will determine if a physician is contacted or not. Regurgitation is frequent in infants because of the frequent feedings, large liquid volume intake, the limited capacity of the esophagus (10 mL in newborn infants), the horizontal position of infants, etc. Infants ingest per kg bodyweight more than twice the volume that adults do (100–150 mL/kg/day compared to 30–50 mL/kg/day) causing more gastric distention and as a consequence more TLESRs.

Although usually regurgitation causes little more than a nuisance, important regurgitation may (seldom) result in caloric insufficiency and malnutrition. Poor weight gain is a crucial warning sign that necessitates clinical management, but it occurs seldom in otherwise healthy infants with GER, and necessitates clinical management (Table 33.2). These infants need a complete diagnostic workup. Hospitalization is often needed. There may be abnormal sucking and swallowing. These infants have no apparent malformations, and may be diagnosed as suffering “non-organic failure to thrive” (“NOFTT ”), a “disorder” that sometimes is attributed to social/sensory deprivation, socioeconomic or primary maternal-child problems. Poor weight gain, feeding refusal, back-arching, irritability, and sleep disturbances have been reported to be related as well as unrelated to GERD [1, 2, 21].

The symptoms of CMPA overlap with many symptoms of GER, or may coexist or complicate GERD [26]. An association between GER and cow milk “hypersensitivity ” was observed in infants and children with severe GER(D) [22]. Esophageal impedance showed that the incidence of nonacid postprandial reflux was decreased after a feeding with an amino acid-based formula compared to standard cow milk-based infant formula [23]. However, this may as well be related to CMPA as to a more rapid gastric emptying. An extensive hydrolysate was shown to reduce esophageal acid exposure in preterm infants with feeding intolerance and reflux symptoms [24]. We showed that a non-thickened or thickened extensive hydrolysate were equally effective in infants presenting with frequent regurgitation and with a positive cow’s milk challenge test [25]. However, in infants included in the same study but with a negative challenge test, the thickened hydrolysate was more effective in obtaining a reduction of episodes of regurgitation compared to the non-thickened hydrolysate [25].

GERD occurs much less frequent than regurgitation in infants; therefore, anti-reflux medication is not often needed [1, 2, 18]. The same amount of distress and crying may be evaluated by some parents as easily acceptable while it will be unbearable for other parents. There is substantial individual variability and some healthy infants may cry up to 6 h a day. In infants, crying, irritability, sleep disturbance, and “colicky symptoms” have long been considered as heartburn equivalents. Irritability may accompany regurgitation and vomiting; however, in the absence of other warning symptoms, irritability and distress are not an indication for extensive testing or for treatment of GERD [1, 18]. The duration of crying is not related with the severity of acid reflux [21]. A meta-analysis concluded that proton pump inhibitors do not decrease crying and distressed behavior in infants [26]. Many factors, such as colic, constipation, CMPA, and neurologic disorders, among many others, may cause infant irritability and GER(D) in a subgroup of infants. There is substantial individual variability and some healthy infants may cry up to 6 h a day.

In adults, “non-erosive reflux disease” (“NERD ”) is a general accepted entity. Again in adults, impaired quality of life, notably regarding pain, mental health, and social function, has been demonstrated in patients with GERD, regardless of the presence of esophagitis [27]. The developing nervous system of infants seems susceptible to pain (hyper-)sensitivity when in contact with acid despite the absence of tissue damage. Some adults “learn to live with their symptoms” (only half of the heartburn complainers seek medical help, although 60 % takes medications) and acquire tolerance to long-lasting symptoms. A relation between GER, GERD, and feeding refusal has not been established in infants. There is no evidence that routine acid-suppressive therapy is effective in infants who present only with distress and irritability.

Heartburn is the predominant GER symptom in adults, occurring weekly in 15–20 % and daily in 5–10 % of subjects. While the verbal child can communicate pain, descriptions of the intensity, location, and severity may be unreliable until the age of at least 8 years, and sometimes later [4].

Esophagitis is defined as visible breaks of the esophageal mucosa [1]. Histology is recommended to rule out complications such as Barrett esophagus or other causes of esophagitis such as eosinophilic esophagitis. Differences in patient recruitment, availability of endoscopy, definition of esophagitis, and self-treatment make it virtually impossible to estimate the incidence of esophagitis.

Odynophagia usually represents esophageal inflammation. Children with GER symptoms present esophagitis in 15 up to 62 %, Barrett’s esophagus in 0.1–3 %, and refractory GERD requiring surgery in 6–13 % [1, 28]. Erosive esophagitis in 0–17-year-old children with GERD-symptoms was reported to be 12.4 %, and increasing with age [29]. The median age of the group with erosive esophagitis was 12.7 ± 4.9 years, versus 10.0 ± 5.1 years in those without erosive esophagitis [29]. The incidence of erosive esophagitis was only 5.5 % in those younger than 1 year [29]. But, of course, patient selection and recruitment, differences in definition of esophagitis, and availability of self-treatment determine these data.

In nonverbal infants, behaviors suggesting esophagitis include crying, irritability, sleep disturbance, and “colic.” However, while the incidence of infantile colic is about 20 % [6], the incidence of esophagitis at this age is only 5 % [29, 30]. As a consequence, infant crying is not an indication for acid-reducing treatment. Infants may also appear very hungry until their first swallows and then become irritable and refuse to drink.

Dysphagia is linked to a stricture or esophagitis, both eosinophilic and reflux-related. Eosinophilic esophagitis (EoE) is a chronic immune-/antigen-mediated esophageal inflammatory disease associated with esophageal dysfunction resulting from severe eosinophil-predominant inflammation. The reasons for the impressive rise in the prevalence of EoE are still poorly understood. Atopic features, allergic symptoms, or positive allergic tests are reported in more than 90 % and peripheral eosinophilia in 50 % of patients although these findings depend on patient selection. A genome-wide association study on 351 patients with EoE identified the 5q22 locus encoding TSLP and WDR36 as an EoE susceptibility locus [31]. However, environmental factors may be more relevant than genetic susceptibility [32]. At endoscopy, a pale, granular, furrowed, and occasional ringed esophageal mucosa and, in more severe cases, esophageal stenosis may even appear [1]. But the esophageal mucosa may also appear visually normal, what highlights the importance of histology. The hallmark of EoE is an eosinophilic infiltrate of >15 eosinophils per high power field (HPF ) whereas, in reflux esophagitis, the eosinophils are in general limited to less than 5/per HPF. Similarly to reflux esophagitis there is no specific symptom of EoE but dysphagia for solids is often reported in older children, while symptoms in infants are more reflux-like including vomiting, regurgitation, feeding refusal, and failure to thrive [33]. The overlap between GERD and EoE is well recognized and failure of PPI treatment is a prerequisite to diagnose EoE [33].

In reflux esophagitis, the distal and lower eosinophilic infiltrate is in theory limited to less than 5 per high power field (HPF) with 85 % positive response to GER treatment, compared to primary EoE with >20 eosinophils per HPF. Demonstration of failure of PPI treatment as a condition needed to diagnose EoE brought reflux esophagitis back in the picture [33, 34].

Many extra-esophageal manifestations such as asthma, pneumonia, bronchiectasis, ALTE (apparent life-threatening event), laryngotracheitis, and sinusitis are reported to be associated with GER. However, the paucity of studies, small sample sizes, and varying disease definitions did not allow to draw firm conclusions [17]. Different pathophysiologic mechanisms are direct aspiration, vagal-mediated bronchial and laryngeal spasm, and neural-mediated inflammation.

Neurologically impaired children accumulate many risk factors for severe GERD: spasticity or hypotonicity, supine position, constipation, etc. (see Chap. XX). Diagnosis of reflux disease in these children is often difficult because of their underlying conditions. Whether this group of patients has more severe reflux disease, or has less effective defense mechanisms, or presents with more severe symptoms because of the inability to express and/or recognize symptoms at an earlier course of the condition remains open for debate. Response to treatment, both medical and surgical, is poor in the neurologically impaired child compared to the neurologic normal child.

Children with congenital abnormalities or after major thoracic or abdominal surgery are at risk for developing severe GERD. Children with anatomic abnormalities such as hiatal hernia, repaired esophageal atresia, and malrotation have frequently severe GERD [62]. Gastroesophageal problems in children born with esophageal atresia are common (see Chap. XXX). Routine follow-up with endoscopy and pH metry in esophageal atresia patients is warranted [63]. GERD in these children is often refractory to medical treatment and requires antireflux surgery. However, the high rates of wrap failure invite close follow-up in all cases and reoperation or other measures whenever necessary [64].

Although there is abundant literature on overweight and increased GER in adults, data in children are scarce. There are no data in literature that preterm babies have more (severe) reflux than term born babies, although many preterm babies are treated for reflux. The role of reflux in patients with bronchopulmonary dysplasia and other chronic respiratory disorders is not clear.

Severe complications of GERD such as Barrett’s esophagus and esophageal adenocarcinoma are seldom in otherwise healthy children. If these severe complications are found, they occur mainly in “at-risk” populations such as esophageal atresia and neurologically handicapped children. Barrett’s esophagus is a premalignant condition in which metaplastic specialized columnar epithelium with goblet cells is present in the tubular esophagus. Differences in esophageal mucosal resistance and genetic factors may partially explain the diversity of lesions and symptoms. In a series including 402 children with GERD without neurological or congenital anomalies, no case of Barrett’s esophagus was detected [28]. In another series including 103 children with long-lasting GERD, and not previously treated with H₂ receptor antagonists (H₂RAs) or a proton pump inhibitors (PPIs), Barrett’s esophagus was detected in 13 %. Reflux symptoms during childhood were not different in adults without than in adults with Barrett’s esophagus [65]. Barrett’s esophagus has a male predominance, and increases with age. Patients with short segments of columnar-lined esophagus and intestinal metaplasia have similar esophageal acid exposure but significantly higher frequency of abnormal bilirubin exposure and longer median duration of reflux symptoms than patients without intestinal metaplasia [66]. There is a genetic predisposition in families in patients with Barrett’s esophagus and esophageal carcinoma [1].

Peptic ulcer and esophageal and gastric neoplastic changes in children are extremely seldom. In adults, a decreased prevalence of gastric cancer and peptic ulcer with an opposite increase of esophageal adenocarcinoma and GERD has been noted over the last 30 years [67]. This has been attributed to independent factors amongst which are changes in dietary habits such as a higher fat intake, an increased incidence of obesity, and a decreased incidence of Helicobacter pylori infection [67]. Among adults with long-standing and severe reflux the odds ratios are 43.5 for esophageal adenocarcinoma and 4.4 for adenocarcinoma at the cardia [68]. It is unknown whether mild esophagitis or GER symptoms persisting from childhood is related to an increased risk for severe complications in adults.

Diagnostic procedures are not discussed in detail. History in children is difficult and considered poorly reliable up to the age of minimally 8 or even 12 years old [1]. History is still “the first and most important thing to do” but it is obvious that history has also its limitations. A GER questionnaire score or “response to PPI” does not accurately diagnose GERD [69]. Orenstein developed the “infant GER-questionnaire” [70], intended to result in an objective, validated, and repeatable quantification of symptoms suggestive for GERD. The I-GER was revised (the “I-GERQ-R”) in 185 patients and 93 controls, resulting in an internal consistency and test-re-test reliability of over 0.85 [71]. However, Aggarwal and coworkers obtained with the same I-GER-Q a sensitivity of only 43 % and a specificity of 79 % [72]. Moreover, pH metry results were not different according to a “positive” or “negative” score of the I-GER-Q [72]. Vandenplas and coworkers showed that not one question was found to be significantly predictive for the presence of esophagitis. The I-GERQ cutoff score failed to identify 26 % of infants with GERD (according to pH metry results or presence of esophagitis) and was positive in 81 % of infants with a normal esophageal histology and normal pH metry results [73]. Deal et al. developed two different questionnaires, one for infants and one for older children, and showed that the score was higher in symptomatic than in asymptomatic children [74]. In other words: the correlation between questionnaires and results of reflux investigations is poor.

Barium contrast radiography, nuclear scintiscanning, and ultrasound are techniques evaluating postprandial reflux. Normal ranges have not been established for any of these procedures. There is broad consensus that barium studies are not recommended as first-line investigation to diagnose GER(D), although it is in many centers the only diagnostic technique available.

Modern endoscopes are so miniaturized that scope preterm infants of less than 1000 g has become technically easy. There is a poor correlation between the severity of symptoms and presence and absence of esophagitis. In children with reflux-related cough, dilated intercellular space diameter appears to be an objective and useful marker of esophageal mucosal injury regardless of acid exposure, and its evaluation should be considered for those patients where the diagnosis is uncertain [23]. Biopsies of duodenal, gastric, and esophageal mucosa are mandatory to exclude other diseases [1]. Histology is also necessary to distinguish reflux from eosinophilic esophagitis.

Manometry does not demonstrate reflux, but is of interest to analyze pathophysiologic mechanisms causing the reflux, mainly by visualizing and measuring TLESRs, and is indicated in the diagnosis of specific conditions such as achalasia [1].

Esophageal pH metry remains the best method to measure acid in the esophagus, but not all reflux causing symptoms is acid and not all acid reflux is causing symptoms (see Chap. XX). While the Bravo-capsule is popular in the USA, it is hardly used in other parts of the world. Although normal ranges have been established for pH metry, they are nowadays of limited value since these are hard- and software dependent [11]. The demonstration of a time-association between GER episodes and symptoms is one of the major indications for this technique, which has in fact been poorly used for pH metry.

Multiple intraluminal impedance (MII ) measures electrical potential differences (see Chap. XX). As a consequence, the detection of reflux with MII is not pH dependent, but in combination with pH metry it allows detection of acid (pH < 4.0), nonacid or weakly acid (pH 4.0–7.0), and alkaline reflux (pH > 7.0). It also measures the esophageal height of the refluxate. The optimal time frame to be considered as “time-association” and the optimal parameter to calculate a significant association are still debated. Interestingly, pH-only episodes, reflux episodes detected with pH metry but not with MII (drop in pH without bolus movement), occur relatively frequent [75]. pH-only events occur mainly during the night and in young infants. A good correlation between manual and automated analysis of MII baselines was found [76]. Distal compared to proximal esophageal MII baselines were significantly lower in children with a positive overall pH-MII outcome [77]. During the last 3–5 years, interest has focused on baseline impedance which was shown to be lower in esophagitis, and treatment of esophagitis with PPI does increase baseline impedance [78]. Baseline impedance is reported to be age dependent, what is likely to be related with the size of the esophagus [79, 80]. Moreover, since esophagitis does decrease the baseline, and since the definition of an impedance reflux is a decrease of impedance with >50 %, severe esophagitis may have a normalizing effect on interpretation of MII tracings. If the baseline is already very low, there will be fewer episodes in which the impedance still decreases with >50 %. MII-pH monitoring does increase the sensitivity to diagnose GERD; however, when used alone, it results in poor specificity in patients without acid-suppressive therapy [69].

Each GER investigation technique measures different aspects of reflux. Therefore, it is not unexpected that the correlation between the results of the different techniques is poor. There is no “always-best” investigation technique. Endoscopy is the only diagnostic tool to identify esophagitis; 24-h pH metry measures acid GER and MII detects all GER episodes.

The labeling of an otherwise healthy infant as having a “disease” increases parents’ interest in medicating unnecessarily their infant [81]. The use of disease labels may promote overtreatment by causing people to believe that ineffective medications with adverse effects are both useful and necessary [81].

Therapeutic options start with reassurance, followed by nutritional management and positional adaptations, and medication (mainly acid reducing) to end with surgery. Therapeutic intervention should always be a balance between intended improvement of symptoms and risk for side effects (Table 33.3).