Generally, only parental education, anticipatory guidance, and modification of feeding composition, frequency, and volume are necessary for the management of uncomplicated infant GER (208,420). Overfeeding exacerbates recurrent regurgitation and should be avoided (211). In some infants with persistent regurgitation, a thickened or commercial antiregurgitation formula may help control the frequency of regurgitation (Section 4.1.1). There is no evidence that antisecretory or promotility agents improve physiologic infant regurgitation. Prone positioning is not recommended because of its association with SIDS. Because regurgitation is sometimes the sole manifestation of cow's milk protein allergy in healthy-looking infants (420,421), a 2-week trial of protein hydrolysate– or amino acid–based formula or a trial of milk-free diet for the breast-feeding mother is appropriate in infants not responding to previous management.
The infant with recurrent regurgitation and poor weight gain should not be confused with the “happy spitter” described in Section 6.1.1. Whereas the history and physical examination may be identical, poor weight gain is not typical of uncomplicated infant GER and is a crucial warning sign that alters clinical management.
Because there are no well-controlled studies evaluating diagnostic or therapeutic strategies for these infants, the following approach is based on expert opinion (Fig. 2). A feeding history should be obtained that includes an estimate of energy offered and ingested per day, an estimate of energy loss through regurgitation, a description of formula preparation and feeding schedule, an assessment of breast milk sufficiency, and a description of infant sucking and swallowing behavior. Parents should be advised not to reduce intake to the point of energy deprivation in the attempt to prevent regurgitation. If problems identified by history seem to explain the symptoms and can be addressed, close outpatient monitoring of weight gain will determine whether further evaluation is indicated.
If chronic regurgitation and inadequate weight gain persist after observation and despite adequate energy intake, evaluation for causes of failure to thrive compatible with the history is mandatory. Among possible etiologies in infancy are infections (especially urinary tract), food allergy, anatomic abnormalities, neurologic disorders, metabolic disease, and neglect or abuse (Table 4). A 2- to 4-week trial of extensively hydrolyzed or amino acid–based formula is appropriate. Depending on the results of investigations and response to dietary management, the infant should be referred to a pediatric specialist. Hospitalization for observation and testing is appropriate in some infants with persistent failure to thrive. Nasogastric or nasojejunal feeding is occasionally necessary to achieve weight gain in the infant with no other clear explanation for poor weight gain (231).
Irritability and regurgitation are nonspecific symptoms that occur in healthy infants and are associated with a wide range of physiologic and pathologic conditions. For example, exposure to environmental factors, such as tobacco smoke may result in irritability in infants (422,423). Healthy young infants fuss or cry an average of 2 hours daily. There is substantial individual variation and some healthy infants cry as much as 6 hours per day. Likewise, there is variation in parental perceptions regarding the severity and duration of crying and its importance. The amount of daily crying typically peaks at 6 weeks of age (424,425). As with fussing, sleeping patterns of healthy infants show great individual and maturational variation as do parental expectations for sleep behavior (426).
The concept that infant irritability and sleep disturbances are manifestations of GER is largely extrapolated from adult descriptions of heartburn and sleep disturbances that improve with antacid therapy (50,427–429). Although 1 study in infants showed a correlation between infant grimacing and episodes of reflux (430), multiple other studies have shown no relation between crying and GERD determined by esophageal pH testing (61,84,140,431) or the presence of esophagitis (47,84). Some small descriptive studies have evaluated pH probe studies in infants with irritability and sleep disturbance. One compared infants with normal and abnormal pH probe studies and found a slight increase in nighttime waking, delayed onset of sleep, and greater daytime sleeping in those with abnormal pH probe studies (432). Another study found no increase in sleep disturbance in infants with abnormal esophageal pH tests (431). One dual pH probe study showed slightly poorer proximal acid clearance in colicky infants, but no abnormality in other parameters (433). Recently, a study of colicky infants found abnormal pH test results only in those with excessive regurgitation or feeding difficulties (61).
There are few studies addressing the appropriate management of infants with irritability and reflux symptoms. One study showed a greater decrease in crying time in infants treated with a 1-mg/kg dose of famotidine than in infants given 0.5 mg/kg. Although the authors concluded from this study that famotidine was effective in treating infant crying, differences in age between treatment groups, absence of placebo control, and a lack of difference between the treatment group and a group withdrawn from medications cast doubt on this conclusion (293). Placebo-controlled studies have evaluated acid-suppressive therapy in irritable infants. A study of infants with irritability and normal esophageal pH tests found that combined ranitidine and cisapride treatment was not superior to placebo or counselling for persistent crying (45). A double-blind placebo-controlled trial of omeprazole in irritable infants who either had esophagitis or an RI >5% found no difference in crying between treated and placebo groups despite highly effective acid suppression in the treated group (46). A large double-blind study of 162 infants randomized to 4 weeks of placebo or lansoprazole showed an identical 54% response rate in each group, using an endpoint of >50% reduction of measures of feeding-related symptoms (crying, irritability, arching) and other parameters of the I-GERQ questionnaire (9). Furthermore, this study showed a small but significant increase in the numbers of infants that experienced lower respiratory symptoms during the treatment trial.
The available evidence does not support an empiric trial of acid suppression in infants with unexplained crying, irritability, or sleep disturbance. A symptom diary (61,434) or hospital observation (45,435) may be useful to confirm the history, which is subjective to observation bias.
Disorders other than GERD that are likely to cause irritability include cow's milk protein allergy (142,436), infections (especially of the urinary tract), constipation, respiratory disorders, congenital or acquired neurologic abnormalities (437), metabolic disease, surgical emergencies (eg, intermittent volvulus, ovarian torsion), cardiac disease, corneal abrasion, bone fractures, hair tourniquet syndrome, tobacco smoke exposure, hunger, abuse, or neglect (438,439). Allergy to cow's milk protein or other formula intolerance may cause infant irritability, distress, and vomiting indistinguishable from GER. In 1 controlled study, an empiric trial of formula made with partially hydrolyzed whey proteins, prebiotic oligosaccharides, and a high β-palmitic acid content significantly decreased colic (440). Data on the efficacy of extensively hydrolyzed formulae in infants with unexplained crying and/or distressed behavior are limited (441,442). An empiric 2- to 4-week trial of an extensively hydrolyzed formula (1 that has been validated as being tolerated by at least 90% of infants with cow's milk protein allergy with 95% confidence) or amino acid–based formula may be indicated in irritable infants after diagnostic evaluations have been performed for other conditions causing irritability. Reflux is an uncommon cause of irritability or unexplained crying in otherwise healthy infants. However, if irritability persists with no explanation other than suspected GERD, expert opinion suggests the following options. The practitioner may continue anticipatory guidance and training of parents in the management of such infants with the expectation of improvement with time. Additional investigations to ascertain the relation between reflux episodes and symptoms or to diagnose reflux or other causes of esophagitis may be indicated (pH monitoring ± impedance monitoring, endoscopy). A time-limited (2-week) trial of antisecretory therapy may be considered, but there is potential risk of adverse effects, and clinical improvement following empiric therapy may be due to spontaneous symptom resolution or a placebo response. The risk/benefit ratio of these approaches is not clear.
Physiologic regurgitation, episodic vomiting, or regurgitation followed by swallowing of refluxate in the mouth are frequent in infants. Whether of new onset or persisting from infancy, these symptoms are less common in children older than 18 months of age. Although these symptoms are not unique to GERD, evaluation to diagnose possible GERD and to rule out alternative diagnosis is recommended based on expert opinion. Testing may include upper GI endoscopy, and/or esophageal pH/MII, and/or barium upper GI series (Table 4).
Heartburn or substernal burning pain is a symptom of GERD with or without esophagitis (443). Recent consensus statements suggest that typical heartburn is a reliable indicator for GERD in adolescents and adults if it is the dominant symptom (13,50). One study in adults found that dominant heartburn had a positive predictive value of 81% for GERD determined by pH study (444), but other studies have not confirmed this close association between history and test results (378). Esophageal pH probe results are normal in one third of adults with chronic heartburn, even those whose heartburn is reproduced by esophageal acid perfusion and those who respond favorably to antacids. Some adults with heartburn and normal pH studies have endoscopically proven esophagitis (445). In older children and adolescents the description and localization of heartburn pain is probably reliable. In young children, however, symptom descriptions and localization may be unreliable (56–60,446).
No randomized placebo-controlled studies evaluate lifestyle changes or pharmacologic therapy of heartburn in children or adolescents. Case series have shown that PPI therapy relieves heartburn symptoms in adolescents (55,64,447). Expert opinion suggests using a management approach to heartburn in older children and adolescents similar to that used in adults (Fig. 3). Other causes of heartburn-like chest pain including cardiac, respiratory, musculoskeletal, medication-induced, or infectious etiologies should be considered. If GERD is suspected as the most likely cause of symptoms, lifestyle changes, avoidance of precipitating factors, and a 2- to 4-week trial of PPI are recommended (446,448–450). If there is no improvement following empiric therapy, the older child or adolescent should be referred to a pediatric gastroenterologist for diagnostic evaluation. If improvement follows PPI therapy and lifestyle changes, treatment can be continued for 2 to 3 months. In some patients, abrupt discontinuation of treatment may result in acid rebound that precipitates symptoms; therefore, it is recommended that antisecretory therapy be weaned slowly (451,452). If symptoms recur when therapy is weaned or discontinued, upper endoscopy may be helpful to determine the presence and severity of esophagitis and differentiate reflux-related esophagitis from nonreflux pathologies such as infection or EoE that may present with heartburn (40,453) Because chronic heartburn can have a substantial negative impact on quality of life, long-term therapy with PPIs may be required, even in the absence of esophagitis (454,455). Extrapolation from adult data suggests that in older children and adolescents, on-demand or intermittent therapy with antacids, H2RA, or PPIs may be used for occasional symptoms of heartburn (302,455,456).
In open-label studies of children with erosive esophagitis, PPIs produced healing in 78% to 95% with 8 weeks of therapy and in 94% to 100% with 12 weeks of therapy. Symptoms improved in 70% to 80% of the group treated for 12 weeks (130,312,447). Most patients in these studies had lower grades of erosive esophagitis, and the studies did not include patients with underlying conditions such as NI, repaired tracheoesophageal fistula, chronic lung disease, or HH. PPIs have been shown to heal higher grades of esophagitis (grades 3–4) in children with these underlying conditions, even in some when esophagitis had been refractory to treatment with H2RAs, prokinetic agents, and even antireflux surgery (28,29,131). However, in these selected cases resistant to standard management, high per-kilogram dose and long duration of therapy (up to 6 months) may be required for healing and symptom control (28,29,131).
In uncontrolled studies of children with erosive and nonerosive disease treated with PPIs, 70% experienced relief of “typical symptoms of GERD,” that is, heartburn (312,447). A significant percent of patients remained symptomatic, albeit at lower intensity. Suboptimal symptom relief may be due to large per-kilogram dosing variation. Studies in adults have shown generally poorer therapeutic response to PPI in patients with NERD compared with patients with erosive esophagitis (457,458).
With regard to maintenance therapy, in a prospective study of children whose erosive esophagitis had healed following 3 months of omeprazole therapy, only half maintained the remission of symptoms and endoscopic disease in a maintenance phase during which they received half the healing dose of PPI (316). In another study, patients whose erosive esophagitis healed after 3 months' omeprazole treatment (1.4 mg · kg−1 · day−1) underwent double-blind randomization into 3 groups, receiving either maintenance therapy with omeprazole at half the healing dose, ranitidine, or placebo for 6 months (130). In all 3 groups, few patients had a relapse of symptoms or of endoscopic esophagitis during or after maintenance therapy. There were important differences between these 2 studies. Specifically, in the first study, the mean grade of esophagitis was higher, and 41% of patients had an underlying disorder predisposing to GERD. In a retrospective study of 166 children with erosive esophagitis unable to withdraw from PPIs for up to 11 years (median 3.5 years), 79% had at least 1 underlying condition predisposing them to GERD and 39% had HH (28). Thus, patients with lower grades of erosive esophagitis and without an underlying high-risk condition may not require long-term PPI therapy after initial effective treatment. In a recent study of adults with long-term PPI use, 27% were able to discontinue drug without relapse (452).
PPIs are recommended as initial therapy in children with erosive esophagitis. Initial treatment for 3 months is advised. If adequate control of symptoms is not achieved within 4 weeks, the dose of PPI can be increased. Patients who require higher PPI dose to control symptoms and produce healing are those with conditions that predispose to severe-chronic GERD and those with higher grades of esophagitis or BE. In most cases, efficacy of therapy can be monitored by extent of symptom relief without routine endoscopic follow-up. Endoscopic monitoring of treatment efficacy may be useful in patients whose presenting signs and symptoms are atypical, who have persistent symptoms while taking adequate acid-suppressive drugs, or who had higher grades of esophagitis or esophageal stricture at presentation (see also Section 5.2.2). Follow-up endoscopy is not routinely indicated in patients with nonerosive disease, particularly if they are asymptomatic on medication.
Most patients require only 1 daily dose of PPI to obtain symptomatic relief and heal esophagitis (29,131,447,459). The optimum dosage regimen is to administer a once-daily dose 15 to 30 minutes before the first meal of the day. It is not necessary to make patients achlorhydric to relieve symptoms or heal esophagitis, and, in light of the data on infectious and other complications of acid suppression by H2RAs or PPIs, it is probably not desirable to do so.
The prevalence of BE is much lower in children than adults, but it does occur in children with severe-chronic GERD. In 1 group of children with severe-chronic GERD, columnar metaplasia was present in 5% and columnar metaplasia with goblet-cell metaplasia was present in another 5% (28). Accuracy of diagnosis has important implications for longevity and surveillance. The diagnosis of BE is both overlooked and overcalled in children (28,134). Therefore, the primary task of the gastroenterologist is accuracy of diagnosis, especially in light of the proposed new criteria for the diagnosis of BE in children and adults (13,50). If esophagogastric landmarks are obscured by bleeding and exudate, a course of high-dose PPI for at least 12 weeks before making a diagnosis is advised to allow for better visualization of anatomic landmarks and to remove the histologic changes of chronic inflammation that may confuse the diagnosis. After PPI therapy, multiple biopsies should be taken to characterize the type of BE and to rule out dysplasia (134,148).
Dysphagia, or difficulty in swallowing, occurs in association with oral and esophageal anatomic abnormalities, neurologic and motor disorders, oral and esophageal inflammatory diseases, and psychologic stressors or disorders. GERD is commonly cited as a cause of dysphagia or odynophagia, and although it may be causal in some patients, there are no pediatric data demonstrating this relation, nor has symptom improvement in infants and children been demonstrated with antireflux therapy. In a population-based Australian study, 16% of healthy adults reported having “dysphagia ever” (462). In this study, dysphagia correlated with anxiety and depression but also with GERD (odds ratio 2.96) (462). Another study found dysphagia in 11% of healthy adults and 28% of adults with GERD symptoms (463). In a meta-analysis of 11,945 adults with erosive esophagitis, 37% had dysphagia (464). However, in young adults presenting with dysphagia, radiographic evaluation demonstrated conditions other than GERD in 70% that were more likely causes of the symptoms (465). Dysphagia is a prominent symptom in up to 80% of adults and children with EoE (93,450,466).
Odynophagia, or pain caused by swallowing, must be distinguished from heartburn (substernal pain caused by esophageal acid exposure) and dysphagia. Although odynophagia may be a symptom of peptic esophagitis, it is more often associated with other conditions such as oropharyngeal inflammation, esophageal ulcer, EoE, infectious esophagitis (eg, infection with herpes simplex, candida, or cytomegalovirus), and esophageal motor disorders. A patient with odynophagia may in time develop behaviors around eating that resemble dysphagia. There are no pediatric studies on the relation between GERD and odynophagia.
Patients often find it difficult to distinguish between dysphagia and odynophagia. In the majority of patients with dysphagia, the dysphagia is not caused or related to reflux disease. The present literature indicates that dysphagia is frequent among patients with EoE. In those relatively uncommon patients in whom GERD causes dysphagia, esophagitis is often present. Expert opinion suggests that odynophagia may be associated with peptic esophagitis and esophagitis of other causes.
Feeding refusal and feeding difficulty are terms used mainly to describe the following infant symptoms: refusal to eat, uncoordinated sucking and swallowing, gagging, vomiting, and irritability during feeding. A relation between GER or GERD and feeding refusal has not been established. Although older case series suggest that reflux disease caused infant feeding difficulty, no prospective studies have proven causation and none have shown resolution with GERD therapy (467). One retrospective study found a higher incidence of poor intake, decreased feeding readiness, and food refusal in infants with abnormal pH probe tests than in normal case controls (468). Another study found no association between GERD diagnosed by pH probe and feeding difficulty, except in infants who also had excessive regurgitation (61). A double-blind placebo-controlled trial showed no improvement in feeding difficulties following lansoprazole therapy compared with placebo in infants with suspected GERD (9). A recent study found that anorexia or feeding refusal was occasionally a symptom of erosive esophagitis in children 1 to 5 years of age (40).
An upper GI contrast study is useful but not required for the infant with feeding refusal or difficulty or the older child reporting dysphagia. Its major use is to identify a non-GERD disorder such as achalasia or foreign body or to identify esophageal narrowing from a stricture. The upper GI contrast study or a more focused videofluoroscopic swallowing study that evaluates the mechanisms of feeding and swallowing may be helpful to identify nonesophageal causes of feeding difficulties, especially in infants and younger children. In children and adolescents who report dysphagia or odynophagia in combination with esophageal symptoms, endoscopy with biopsy is useful to distinguish among causes of esophagitis.
There is no evidence that supports a causal relation between infant feeding difficulties and GER or GERD. In the infant with feeding refusal, acid suppression without earlier diagnostic evaluation is not recommended. Direct observation focused on neurologic, behavioral, metabolic, and infectious disease is essential for the evaluation and diagnosis of this symptom complex (469). In the older child or adolescent empiric antisecretory therapy is only recommended if there are additional symptoms or findings suggesting GERD.
The literature on the relation between apnea, respiratory pauses, apparent life-threatening events (ALTEs) or SIDS, and reflux is conflicting, in large part because of the different criteria used to define breath stoppage, the various methods used to measure reflux and respiratory pauses, and the different populations studied.
A recent study combining data from simultaneous esophageal pH/MII and cardiorespiratory monitoring in infants showed a temporal association between 30% of the nonpathologic, short episodes of central apnea and reflux (115). These findings cannot be extrapolated to pathologic infant apnea and may represent a normal protective cessation of breathing during regurgitation. Recent studies using combined pH/MII have generally detected little relation between apneic spells and reflux episodes (470,471). Some studies have found a relation between long episodes of apnea (>30 seconds) and acid reflux in premature infants (472). In 1 older study, short apnea or bradycardia spells were tightly tied to spells of vomiting or regurgitation, whereas the majority of prolonged apnea spells (>20 seconds) were not (473). In highly selected cases, reflux is clearly associated with pathological, central, and obstructive apnea (241). None of these studies has conclusively shown a cause and effect relation between reflux and pathologic apnea.
ALTEs are frightening episodes in infants characterized by a combination of apnea, color change (cyanosis, pallor, and plethora), abnormal muscle tone (limpness and stiffness), choking, and gagging that require intervention by the observer (474). The identification of a behavior as ALTE is observer dependent (475). The first event usually occurs at 1 to 2 months of age and rarely after 8 months. ALTEs may recur (476,477), and infants with an ALTE are at slightly increased risk for subsequent sudden death (477–482). ALTEs may be associated with infection, child abuse, upper airway obstruction, cardiac, respiratory, metabolic, and neurologic disorders. ALTEs associated with reflux may not be pathologic; some may be an exaggeration of normal protective reflexes that inhibit breathing while the infant retches or while the pharynx is filled with gastric contents.
In older studies, patients with ALTEs had a 60% to 70% prevalence of recurrent regurgitation or emesis (475,477), and abnormal esophageal pH tests were documented in 40% to 80% of patients with ALTEs (483,484). Case reports and series described ALTEs triggered by overt regurgitation into the oropharynx, by aspiration of refluxed gastric contents, and by reflux induced by positional change after feedings (485–488). In selected patients with ALTE, acid perfusion of the esophagus induces obstructive apnea (485) or oxygen desaturation (483), suggesting that 1 mechanism for ALTE is acid stimulation of laryngeal, pharyngeal, or esophageal chemoreceptors with subsequent laryngospasm. In selected infants, a clear temporal relation between apnea and ALTE can be demonstrated. However, large case series have not shown a consistent statistical relation between GER and pathologic apnea or ALTEs (489,490). Larger studies using combined esophageal pH/MII may clarify the extent of these temporal relations.
Poor quality of sleep characterized by irregular breathing patterns is associated with reflux (484,489–496). Although several studies have reported an occasional correlation of GER with short mixed central apneas (5–15 seconds) (492,493,495), all of the patients also had episodes of apnea unrelated to episodes of GER, suggesting a primary impairment in the regulation of respiration.
At present there is no evidence that the characteristics of the ALTE or the polysomnographic record can predict which infants with ALTE are at risk for future life-threatening episodes or sudden death. Although rare, SIDS has been reported to occur in patients with a previous ALTE and documented GER (241,491,497). In none of these patients was a correlation between esophageal acidification and a cardiopulmonary event ever recorded.
The available evidence suggests that in the vast majority of infants, GER is not related to pathologic apnea or to ALTE, although a clear temporal relation based on history, observation or testing occurs in individual infants. Impedance/pH recording in combination with polysomnographic recording is recommended to demonstrate this relation in these infants.
Medical therapy of ALTEs suspected of being GER-related has not been adequately studied. Approaches that decrease the frequency of regurgitation and the volume of reflux such as thickened feeding may theoretically be beneficial. Pharmacotherapy has not been shown to be effective. The occurrence of ALTEs diminishes significantly with age and without therapy in most cases, suggesting that no antireflux therapy is needed. The ALTEs most likely to improve with antireflux therapy are those obviously associated with vomiting or regurgitation, those that occur in the awake infant after feeding, and those characterized by obstructive apnea. Because medical therapy has not been shown to be effective, surgery may be a reasonable approach in the rare infant in whom ALTEs are truly life threatening and are shown to be clearly related to GER.
In some exceptional situations, prone sleeping (with cardiorespiratory monitoring) may be recommended because of a major risk of apnea or aspiration caused by refluxed material.
An etiologic role for reflux in reactive airways disease (asthma) has not been established, although animal and human studies have suggested that reflux may exacerbate existing asthma. Proposed mechanisms by which reflux aggravates asthma are direct production of airway inflammation by aspirated gastric contents, airway hyperresponsiveness triggered by lower airway aspiration of minute amounts of acid, vagally mediated bronchial or laryngeal spasm, and neurally mediated inflammation (498–501). Esophageal acidification in healthy adults has minimal effect on pulmonary function (498); however, esophageal acidification in asthmatic patients can produce airway hyperresponsiveness and airflow obstruction (502).
Few studies have evaluated the impact of asthma on the severity of GERD. Chronic hyperinflation caused by asthma can flatten the diaphragms, alter crural function, and displace the lower esophageal sphincter into the negative atmosphere of the chest, effectively reducing resting LES pressure and causing disappearance of the acute esophagogastric angle of His. Lung hyperinflation and airflow obstruction may produce increased negative intrathoracic pressure, effectively increasing the pressure gradient across the diaphragm and promoting reflux. Although theophylline and β-receptor agonists cause a reduction of resting LES pressure, these drugs have not been linked to the development of GERD in treated asthmatics (503). Oral corticosteroids promote reflux in adults, but the mechanism is unclear (504).
Many studies have demonstrated an association between asthma and measurements of reflux by pH probe or pH/MII. These studies have shown that 60% to 80% of children with asthma have abnormal pH or pH/MII recordings (505). A study of 77 children 3 to 14 years old with difficult-to-control asthma found that 66% had abnormal RI on pH testing (90). In a study of 84 otherwise healthy infants with daily wheezing, 64% had abnormal 24-hour pH studies, and 44% of these had no overt symptoms of GERD (506). Nocturnal wheezing appears particularly related to GERD. One study used combined esophageal pH/MII monitoring and demonstrated a tighter association between reflux episodes and respiratory symptoms than pH monitoring alone (507), but no studies to date have shown that pH/MII studies are useful in identifying those patients whose asthma may respond to antireflux therapy.
One study found omeprazole treatment to be ineffective in improving asthma symptoms, quality of life, lung function, or use of β2 agonists in children with asthma and GERD (508). High-dose prolonged PPI therapy in adult asthmatics has shown minimal or no efficacy. In 1 large double-blind placebo-controlled study of esomeprazole in adult asthmatics, no improvement occurred in morning peak expiratory flow, but posthoc analysis indicated mild improvements in FEV1 among patients with nocturnal asthma symptoms (509). However, patients with known erosive esophagitis or moderate-to-severe GERD symptoms were excluded. Another study showed a 4% decrease in the number of asthma exacerbations and a 14% decrease in the use of oral corticosteroids in adult patients with moderate-to-severe asthma and heartburn treated with lanzoprazole for 24 weeks but no improvement in symptoms, pulmonary functions, or albuterol use (510). One uncontrolled study in children found that children with persistent moderate asthma and reflux who received antireflux treatment including PPI used significantly less medication to control their asthma (511). Another double-blind placebo-controlled study showed no reduction in wheezing among infants treated with lansoprazole versus placebo for 4 weeks, although wheezing was a secondary endpoint and not the primary focus of the study (9). A controlled trial in adults with reflux and asthma evaluated asthma outcomes after 2 years of continuous ranitidine therapy versus antireflux surgery; surgery led to a larger reduction in symptoms and improved overall clinical status, but neither therapy had a clinically meaningful impact on pulmonary function or pulmonary medication use (512). Some uncontrolled case series using nonobjective parameters have shown a dramatic improvement in asthma symptoms in children after antireflux surgery (95).
Although adult studies show only limited, if any, benefit from PPI or surgical therapy, it is possible that selected patients with heartburn, nocturnal asthma, or steroid-dependent, difficult-to-control asthma may derive some benefit. Symptom reporting is less reliable in infants and children than in adults. Therefore, a reasonable approach to evaluation of pediatric patients in whom GERD is suspected of being a contributing or aggravating factor causing wheezing or asthma is shown in Fig. 4. Other causes of wheezing should be ruled out. There is no strong evidence to support empiric PPI therapy in unselected pediatric patients with wheezing or asthma. Finding abnormal esophageal pH exposure by esophageal pH monitoring, with or without impedance, before considering a trial of long-term PPI therapy or surgery may be useful, although the predictive value of these studies for this purpose has not been established. The relative efficacy of medical versus surgical therapy for GERD in children with asthma is unknown.
Recurrent pneumonia and interstitial lung disease may be complications of reflux, presumably as a result of the failure of airway protective mechanisms to protect the lungs against aspirated gastric contents (513). Reflux causing recurrent pneumonia has been reported in otherwise healthy infants and children (96,514,515). In a retrospective series reviewing the causes of recurrent pneumonia in a heterogenous group of 238 children, the primary cause was aspiration during swallowing in 48%, immunologic disorders in 14%, congenital heart disease in 9%, asthma in 8%, respiratory tract anatomic abnormalities in 8%, unknown in 8%, and reflux in only 6% (516). Small case series suggest that reflux may cause or exacerbate interstitial lung disorders such as idiopathic pulmonary fibrosis (517,518), cystic fibrosis (CF) (519,520), or lung transplant (520,521).
No test can determine whether reflux is causing recurrent pneumonia. An abnormal esophageal pH test may increase the probability that reflux is a cause of recurrent pneumonia but is not proof thereof. A normal esophageal pH test cannot exclude reflux as a cause of pneumonia because if airway protection mechanisms are compromised, even brief reflux episodes that are within the normal range, may be associated with aspiration. Aspiration during swallowing is much more common than aspiration of refluxed material (522). Upper esophageal and pharyngeal pH recordings, and combined pH/MII studies have similar limitations and do not improve the ability to predict GER-related pneumonia (523).
Lipid-laden alveolar macrophages have been used as an indicator of aspiration but the sensitivity and specificity as an indicator of GER-related lung disease is poor (187,524–529). Pepsin content of pulmonary lavage fluid has also been used to document aspiration of gastric contents. Pepsin concentration is elevated in pulmonary lavage from patients with reflux (185,186) but there is substantial overlap with controls (187). Nuclear scintigraphy can detect aspirated gastric contents when images are obtained for 24 hours after enteral administration of a labelled meal. One study reporting that 50% of patients with a variety of respiratory symptoms had aspiration on scintigraphy (169) has not been replicated. It is important to recognize that aspiration also occurs in healthy subjects, especially during sleep (171,172) so the threshold for pathologic aspiration of saliva or gastric contents is not established.
No data are available regarding the predictive value of any diagnostic test for determining which patients will respond to either medical or surgical therapy for GERD. Both medical (530) and surgical (97,531) therapy of GERD have been reported to reduce pulmonary symptoms in certain populations of children with recurrent pneumonia. However, in 1 study of children older than 4 years of age, the number of hospitalizations for respiratory related events increased after antireflux surgery (397). Gastrojejunal feeding provides an alternative approach to prevent reflux-related pneumonia in children with severe NI (532). A recent review of children with severe NI and GERD reported that surgical therapy improved several complications but did not alter the risk of pneumonia (533). The potential benefits of antisecretory therapy for neurologically impaired children with recurrent pneumonia must be balanced against the risk that PPI therapy may increase the incidence of community-acquired pneumonia in these patients, as it does in well children (322). A large double-blind placebo-controlled study to determine the role of PPI therapy in the child with NI is lacking.
In many cases the clinician must make management decisions based on inconclusive diagnostic studies with no certainty regarding outcome. In patients with severely impaired lung function, it may be necessary to proceed with antireflux surgery in an attempt to prevent further pulmonary damage, despite lack of definitive proof that reflux is a cause of pulmonary disease. Alternatively, if minimal pulmonary disease is present, consideration of medical therapy with careful follow-up of pulmonary function may be instituted, although the potential benefits versus risks of PPI are unclear. The efficacy of therapies such as lifestyle changes and prokinetics has not been well studied. A trial of nasogastric feeding may be used to exclude aspiration during swallowing as a potential cause of recurrent disease (532). A trial of nasojejunal therapy may help determine whether surgical antireflux therapy is likely to be beneficial.
The data showing a relation between reflux and upper airway disease are weak, consisting mainly of case descriptions. Airway symptoms attributed to reflux in adults include hoarseness (534), chronic cough (535,536), and the sensation of a lump in the throat (globus sensation) (537,538). Affected adults rarely have typical reflux symptoms. Laryngoscopic findings said to be reflux related include erythema, edema, nodularity, ulceration, granuloma, and cobblestoning (539,540). The sensitivity and specificity of these findings to identify reflux-induced disease are poor (541,542), and a study in children showed poor correlation between laryngeal changes and reflux quantitated by pH probe (543). In a descriptive pediatric study, GERD was more prevalent in children with recurrent laryngotracheitis than in controls (544). In a retrospective study of children undergoing otolaryngologic procedures, an association between esophagitis diagnosed by biopsy and recurrent croup, cough, stridor, laryngomalacia, subglottic stenosis, posterior glottic erythema, and posterior arytenoid erythema was observed (545). Increased frequency of daytime reflux has been described in children with hoarseness (546). One study suggested that reflux contributed to the development of subglottic stenosis in children and to poor outcomes after reparative surgery (547). Increased pharyngeal reflux has been observed in children with laryngomalacia (548,549).
Uncontrolled reports in adults and children showed improved upper airway symptoms after antireflux therapy including fundoplication (193,550–554). However, data from several placebo-controlled studies and careful meta-analyses uniformly have shown no effect of antireflux therapy on upper airway symptoms or signs (555–559). One uncontrolled trial reported a reduction in cough following medical antireflux therapy in children (560). However, a double-blind placebo-controlled study showed no difference in the frequency of symptoms of cough or hoarseness among infants treated with lansoprazole versus those treated with placebo (9).
In summary, descriptive studies report detecting and treating reflux in children with chronic laryngeal signs and symptoms. Upper airway edema, erythema, cobblestoning, and granulomas are neither sensitive nor specific for the diagnosis of GERD. Criteria used for assessing laryngeal findings are variable as are the criteria for diagnosing GERD in published reports. Laryngoscopy is indicated in some of these children to rule out anatomic abnormalities such as laryngeal cleft and functional abnormalities such as vocal-fold dysfunction. Data are insufficient to allow recommending a standard approach to diagnosis, treatment, and follow-up. Extrapolation from adult studies suggests that PPIs will not benefit most children with upper airway symptoms.
Reflux has been suggested as a factor contributing to recurrent sinus disease, pharyngitis, and otitis media (561,562). One uncontrolled case series of children with chronic sinusitis suggested that antireflux treatment dramatically reduced the need for sinus surgery (563). Another series demonstrated more episodes during which pharyngeal pH was <6.0 in children with recurrent rhinopharyngitis compared with controls (564). Two epidemiologic surveys, however, found no difference in the number of ear and sinus infections in infants with and without reflux (17,565). Otalgia has been associated with reflux in children and reported to improve with treatment of reflux (566). There is no proven mechanism by which reflux should cause sinusitis, pharyngitis, and otitis, although direct irritation by refluxed material causing pharyngeal tissue edema has been suggested. The lack of controlled studies and animal models of mechanism makes these studies difficult to translate to pediatric practice.
Case reports and a recent systematic review report a causative association between GERD and dental erosion (414). The severity of dental erosions seems to be correlated with the presence of GERD symptoms and in adults with the severity of proximal esophageal or oral exposure to an acidic pH. Young children and children with NI appear to be at greatest risk. One study in adolescents showed that reflux was associated with an increased incidence of erosion of enamel on the lingual surfaces of the teeth (567). In contrast, another study reported no increased incidence of dental erosions in adolescents with abnormal esophageal pH monitoring (568). Factors other than reflux may also cause similar dental erosions; these include juice drinking, bulimia, and racial and genetic factors that affect the characteristics of enamel and saliva. The approach to evaluation and therapy—specifically, the choice of diagnostic tests, duration of therapy, and criteria for cessation of therapy—is unclear. Close consultation with a qualified pediatric dentist is required. The inspection of the oral cavity in search for dental erosions is advisable in patients with known GERD.
Sandifer syndrome (spasmodic torsional dystonia with arching of the back and opisthotonic posturing, mainly involving the neck and back) is an uncommon but specific manifestation of GERD (13,569,570) that must be differentiated from other causes of abnormal movements including seizures, infantile spasms, and dystonia. The mechanisms underlying this disorder are unproven, but the disorder may be a vagally mediated reflex response to esophageal acid exposure. It resolves with antireflux treatment.
Children with certain underlying disorders are at high risk for developing severe-chronic GERD, compared with those who are otherwise healthy. Although the latter do develop GERD, which on occasion may be severe, the prevalence of severe-chronic GERD is much higher in children with certain underlying conditions, such as NI or anatomic abnormalities, such as repaired EA or HH. These children are more likely to require long-term treatment for healing and maintenance (28,372). Complications of severe GERD occur with greatest frequency in children with underlying GERD-provoking conditions (28,31). Performing studies of various GERD therapies in these groups has inherent difficulties because the populations are heterogeneous; many are unable to report symptoms, some have more than 1 condition, and some require medications to be given by feeding tube. These limit the data available to allow evidence-based recommendations on therapy. However, some studies with quantitative endpoints, for example, endoscopic healing, are available (28,29,131).
The increased frequency and severity of GERD among infants and children with NI including developmental delay are well documented (397,571,572). For example, children with cerebral palsy are at particularly high risk for GERD (571,573–575). Similarly, children with certain genetic syndromes such as Cornelia de Lange and Down syndrome are prone to GERD (576).
The high incidence of severe, chronic GERD is multifactorial in etiology. It is likely that in each child, factors unique to the specific diagnosis and clinical status are responsible. Contributing factors that increase reflux frequency and delay esophageal clearance are chronic supine positioning, abnormal swallowing, heightened gag reflex, abnormal sensory integration, delayed gastric emptying, constipation, obesity, skeletal abnormalities, abnormal muscle tone, and medication side effects. The severity of GERD may result from poor self-protective mechanisms and delayed diagnosis caused by difficulties in obtaining an accurate history of symptoms. Treatment should include lifestyle changes tailored to the unique risk factors of the patient. Changes in feeding volume, consistency, and frequency may be helpful, as may positional changes, control of muscular spasticity, and biofeedback. Antisecretory therapy should be optimized. Long-term treatment with PPIs is often effective for symptom control and maintenance of remission of esophagitis (28,577,578). Baclofen may be useful for reduction of vomiting, but care with regard to dosing and side effects is required (346,347). Elemental diet was shown to improve resistant GERD symptoms in 1 small uncontrolled study that did not differentiate EoE from GERD (579).
Descriptive studies suggest that placement of feeding gastrostomy in children with NI, either by open or laparoscopic surgery, increases the risk of subsequent GERD (580,581). Recent surgical studies comparing open and laparoscopic gastrostomy placement suggest that postoperative development of GERD is less common after laparoscopic and percutaneous endoscopic procedures than open surgical procedures (582–584).
Making a clinical diagnosis of GERD in children with NI is hampered by poor communication with the patient and the frequency of atypical presentations such as anxiety, self-injurious behavior, apparent seizures, and dystonia (585). Evaluation of the child with NI requires a high index of suspicion and must not only confirm the diagnosis but also rule out alternative diagnoses. Contrast GI radiographic studies, upper GI endoscopy and biopsy, metabolic and drug toxicity screening, and pH/impedance studies may be required.
Given the morbidity and high failure rates of antireflux surgery in this group, patients whose symptoms are well controlled on medical therapy may not derive additional benefit from antireflux surgery The relative risks versus benefit of antireflux surgery in children with persistent symptoms despite optimized medical therapy have not been clearly defined (397,586). Patients with respiratory complications of GERD appear to benefit most, but a cause-and-effect relation is difficult to establish, and therefore patient selection is difficult (Section 5.3).
Although pediatric data are scarce, in adults, obesity and/or incremental weight gain have been increasingly shown to be associated with a significantly higher prevalence and severity of GERD, BE, and esophageal adenocarcinoma (265–267).
EA has an incidence of 1 in 3000 live births; thus it is an important cause of chronic-severe GERD in pediatric practice. The esophagus in EA is congenitally dysmotile; it is sometimes foreshortened as a result of surgery or stricture, and a HH is often present (28,29,587), especially in long-gap atresia (588). Significant heart disease, tracheomalacia, or gastric outlet obstruction occurs in up to 18% of these children (587).
Of children and young adults with repaired EA, 50% to 95% have GERD symptoms, including dysphagia and pulmonary symptoms (587,589,590). Esophagitis and BE or some form of metaplasia are prevalent (31,134,589,590), and esophageal adenocarcinoma and squamous cancer are reported in children and adults (589,591–594). A long-term study of 272 surviving children with EA observed no cases of esophageal cancer (595). However, the authors of that study and others (587,589) recommended that patients with EA undergo regular endoscopy to screen for BE and esophageal cancer, given the relatively normal longevity of most patients with EA. In the pre-PPI era, several case series demonstrated a benefit from antireflux surgery, but failure rates of fundoplication are high in children with repaired EA. Medical therapy with PPIs is highly effective in patients with EA and GERD (28).
Patients with achalasia are at increased risk for chronic GERD, esophagitis, and BE following treatment by either pneumatic dilation or myotomy (596,597). The benefit of antireflux therapy at the time of myotomy remains controversial (598). All of the patients with a history of achalasia or a history of EA repair require follow-up for possible complications of GERD, because even those who underwent antireflux surgery are at risk (596). The potential utility of endoscopic surveillance has not been evaluated in these patients.
A higher prevalence of GERD and its complications has been reported in patients with a variety of respiratory disorders including bronchopulmonary dysplasia, idiopathic interstitial fibrosis, and most commonly, CF (500,599,600). In 1 study, 27% of patients with CF younger than 5 years old reported GI symptoms suggestive of reflux (heartburn or regurgitation), compared with only 6% of their healthy siblings (519). However, intraesophageal pH studies in children with CF detect a much higher prevalence of pathologic GE reflux (500), that is, reflux is silent in the majority. Reflux may be silent because GI symptoms are truly absent, or symptoms may be relatively ignored by patients with CF because of their plethora of other problems. Some children with CF consider upper GI symptoms such as heartburn, chest pain, and occasional vomiting, to be part of CF, and therefore may not report them; this results in delayed diagnosis and presentation with complications of GERD (31). There are no trials formally evaluating the benefits and risks of GERD treatments in children with CF, but the high incidence of esophagitis and potential risk of adenocarcinoma makes aggressive treatment reasonable. A retrospective review of fundoplication outcome in patients with CF reported that complications requiring repeat surgery occurred in 12%, recurrent GERD symptoms developed in 48%, and only 28% discontinued GERD medications (601).
Bronchopulmonary dysplasia, a chronic lung disease of infancy with varying degrees of alveolar growth arrest, airway branching abnormalities, and peribronchiolar fibrosis, has been associated with GERD (602). However, more recent studies have not confirmed this association (603). Because most of the studies have been cross-sectional or case-control in design, a cause–effect relation remains to be defined.
Severe GERD is common in patients presenting for transplantation, and a high incidence of GERD occurs following lung transplantation in children and adults (521,604). Complications of GERD are a common source of morbidity in patients with transplantation (521). Pneumonectomy seems to contribute to esophageal and gastric motor dysfunction (605). It has been suggested that in the allograft lung, nonimmune-mediated injury because of reflux contributes to the development of bronchiolitis obliterans syndrome (606).
Although reflux episodes may be more common in infants with bronchopulmonary dysplasia, there is no evidence that GERD therapy affects the clinical course or outcome (603,615). GERD is frequently diagnosed by inadequate criteria in the preterm infant. The relative risks, benefits, and indications for GERD therapy are unclear in premature infants. The long-term risk of GERD in premature infants during adulthood is controversial.
The committee is indebted to Sandy Fasold, Inge Sienaert, and Ilse Van Lier for facilitation of meetings and telephone conference arrangements.
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