Need and Purpose: The scarcity of literature and lack of published guidelines on gastroesophageal reflux disease (GERD) from India, have necessitated this review.

Methods: A literature search in PubMed was conducted with regard to epidemiology, clinical features, investigation and management of GERD in children. English language studies published full over the last 20 years were considered and relevant information was extracted.

Results: Nearly half of all healthy babies regurgitate at least once a day by 4 months of age and this subsides in 90% of them by 1 year. In contrast, GERD prevalence increases with age and by adolescence it is similar to adults (20%). While regurgitation in infancy does not need investigation or therapy, ‘empirical’ proton pump inhibitor (PPI) for 4 weeks is justified in older children with classical GERD symptoms. There is no gold-standard investigation for GERD. A pH study with or without impedance is useful in extraesophageal manifestations and endoscopy in esophagitis. Proton pump inhibitors (PPI) play a pivotal role in the management of GERD and its long-term use has been shown to be safe in children. Antireflux surgery plays a minor role due to, its associated morbidity and high failure rate, especially in the high risk group who needs it most.

Conclusions: Regurgitation in infancy need not be investigated unless there are warning features. Empirical PPI therapy is justified in older children and adolescents with typical reflux symptoms. pH study in extraesophageal manifestations and endoscopy for esophagitis are the investigations of choice. PPI is the mainstay of therapy in GERD.

Key words: Endoscopy, Impedance, pH study, Proton pump inhibitors, Regurgitation.

In an elegantly conducted study from India in 602 children of 1-24 months of age, De, et al.[5] showed that the prevalence of regurgitation was 55% at 1-6 months age and it dropped to 15% at 7-12 months of age and further reduced to 10% at 12-24 months of age. All these studies [2-5] suggest that GER is frequently seen in early infancy and it almost disappears by one year of age. Persistence or appearance of regurgitation beyond 18 months of age is suggestive of pathological condition.

However, the prevalence of GERD i.e. symptoms associated with GER is uncommon in younger children. In the West, the prevalence of GERD is almost 20% in the general population [6]. In a study from USA [7] involving 566 children between 3-9 years of age (parental interview) and 615 children between 10-17 years (directly interviewed), pyrosis or heartburn was reported in 1.8% of the 3-9 years age group and 3.5% in the 10 to 17 years age group compared to 22% in adults (>18 years). Hence, the prevalence of GERD slowly increases with age during childhood and becomes quite frequent among young adults.

Presenting symptoms in infants and children are different (Table I) [8]. The majority of infants, who are otherwise healthy, present with regurgitation or vomiting with no failure to thrive or other associated symptoms. These infants are labeled as ‘happy spitters’. In infants with regurgitation, it is important to differentiate physiological GER from other causes of vomiting and GERD (Table I and II). Infants with GERD are associated with growth failure or indirect symptoms of pain due to esophagitis like irritability, feeding difficulty, sleeping difficulties, crying episodes, anemia etc. Rarely apnea or apparent life-threatening events might be a consequence of GERD but their causal relationship has not yet been established convincingly. Chronic respiratory diseases and upper airway problems like sinusitis, otitis media, laryngitis, dental erosion etc. have been described in infants with GERD but the causality and temporal association of these extra-esophageal symptoms have not yet been established [9]. In children and adolescents, symptoms and complications of GERD are similar to those in adults. Commonest symptom in this group is heartburn or substernal pain. Important aspects of history which help in differentiating GERD from other causes of vomiting are given in Table II. A subset of children with underlying disorders like mental retardation, repaired tracheo-esophageal fistula and esophageal atresia etc. are at higher risk of developing severe GERD and listed in Table III [6].

TABLE I	Presenting Symptoms of Gastroesophageal Reflux Disease (GERD)  in Infants and Children [8]

TABLE II Important Aspects of History to Differentiate GER/GERD From Other Causes of Vomiting

TABLE  III  Conditions Predisposing to Severe Gastroesophageal Reflux Disease  (GERD) in Children [6]

There is no gold standard for the diagnosis of GERD. The choice of investigation depends on the clinical situation for which the investigation is asked for.

The approach to infants is illustrated in Fig. 1. In infants, Orenstein’s infant GER questionnaire (i-GERQ) (Table IV) [10] may help in distinguishing GER from GERD. Similarly, Rome III criteria (Table V) [11] can be used to diagnose GER in infants. Orenstein, et al. have developed a symptom-based 11 points questionnaire (I-GERQ GERD) with maximum score of 25 to differentiate GER from GERD and have shown that a score of >7 has 74% sensitivity and 94% specificity in diagnosing GERD in infants. This questionnaire was applied in Indian population [12] and has shown to be easily adaptable and reproducible but had lower diagnostic accuracy (sensitivity of 43% and specificity of 79%) than the original study. Nevertheless, I-GERQ GERD questionnaire, because of its simplicity (takes just 20 minutes to complete) and reproducibility, can be used to segregate those infants who needs empirical therapy or further investigation.

Fig.1 Suggested approach to gastroesophageal reflux in infants [14].

TABLE IV	Diagnostic Criteria of Infant Regurgitation According to the Rome III Classification [11]

TABLE V	GER vs. GERD in Infants. Modified Orenstein’s Infant GER Questionnaire [10].

• Score >7, sensitivity: 74% and specificity: 94% for diagnosing GERD

The approach to older children and adolescents is given in Fig. 2. In older children (> 8 years, who can give proper history), history and physical examination are the most important and the only steps in most cases of GERD. In adults ‘empiric therapy’ of PPI for 2 to 4 weeks is an accepted method of diagnosing GERD with classical symptoms of heartburn with or without regurgitation [13]. Though there is no study of empirical trial of PPI as a diagnostic test in children, an empirical PPI trial of up to 4 weeks is justified in older children and adolescents with classical symptoms of GERD [14]. Diagnostic studies like endoscopy, pH study, barium upper gastrointestinal series are useful when symptoms are not classical and in cases with complicated GERD. In a patient with classical symptoms of GERD, there is no need to confirm the presence of GER by pH study or by endoscopy. However, in patients with extra-esophageal symptoms like respiratory symptoms without any GER symptoms, a pH study is required to document reflux. Similarly, when esophagitis is suspected (pain or blood loss) upper gastrointestinal endoscopywith esophageal biopsy is recommended. However, when there is any suggestion of an anatomical abnormality like intestinal obstruction or dysphagia, barium upper GI series is indicated.

Fig.2 Suggested approach to gastroesophageal reflux disease in older children and adolescent [14].

The basic principle of this technique is to detect the change in electrical resistance (or impedance) that occurs during the passage of a bolus of gas or liquid across a measuring segment (between electrodes) placed in the esophagus. Impedance is inversely proportional to electrical conductivity. Since the conductivity of liquid (high) and air (low) is different, MII can easily differentiate liquid from gas reflux. Moreover, this study detects both acid and non-acid reflux and the direction of reflux (retrograde from stomach to esophagus versus ante-grade bolus movement). The combination of impedance with pH monitoring is shown to be superior to pH-study alone for evaluation of GER-related symptom association [14]. Multichannel intraluminal impedance-pH monitoring (MII-pH) has the advantage of picking up acid, non-acid or weakly acid reflux, the direction of reflux and also to distinguish between liquid, solid and gas reflux in all age groups[14-16].Indications of MII-pH study are same as a pH-study [14]. The limitations of MII-pH study are; high cost, limited availability, limited therapeutic implications (clinical relevance of measuring non-acidic reflux remains doubtful) and the lack of evidence-based parameters for assessment of GER [16].

Upper gastrointestinal endoscopy is the best method of detecting esophagitis as a consequence of GERD. However, normal endoscopy (found in 60% to 80% cases of GERD in children) [17] does not rule out GERD and this type of GERD is called Non-erosive reflux disease (NERD). Endoscopy needs to be combined with a biopsy to increase the diagnostic yield (especially in NERD) and to rule out other causes of esophagitis (like eosinophilic esophagitis, Crohn’s disease etc). Indications of endoscopy are; persistence of symptoms despite therapy, dysphagia or odynophagia, evidence of GI bleeding or iron deficiency anemia, stricture or ulcer on barium study and long duration GERD to detect Barrett’s esophagus. Advantages of endoscopy are; it gives a direct information about the presence and severity of esophagitis, detects complications like ulcer, stricture, Barrett’s esophagus, documents healing of erosive esophagitis after therapy and endoscopic esophageal biopsy helps to exclude other cause of esophagitis. Histology is more sensitive than endoscopy in the early stage (non-erosive stage). Erosive esophagitis is the most definite evidence of GERD on endoscopy. Hence, if there is no erosion or mucosal break on endoscopy, biopsy (2 cm proximal to gastroesophageal junction) helps to establish the diagnosis of GERD. The most important features of GERD on esophageal histology are; basal zone hyperplasia (>20% of total thickness) and elongation of papillae or rete pegs (>50% of total thickness). Other histological features are; infiltration with neutrophils or eosinophils (<15/high power field), growing of blood vessels in papilla etc [18,19]. Nevertheless, recent studies have shown that histological changes are neither sensitive nor specific for reflux disease in NERD cases and should not be used alone to diagnose or exclude GERD [14].

This test is useful to detect anatomical anomalies but is not useful in diagnosing GERD. The sensitivity and specificity of barium study to diagnose GERD is less than 50% [20,21]. It cannot differentiate physiological from pathological reflux. Hence, it is not recommended for the diagnosis of GERD [14].

Technetium labeled milk scan is a non-invasive test but has poor sensitivity and specificity. The only situation where it may be useful is recurrent pneumonia due to aspiration of gastric contents. Retention of radioactivity in lungs beyond 24 hours suggests GERD as a cause. However, absence of radioactivity in the lungs does not rule out GERD. Nuclear scintigraphy is not recommended for the routine evaluation of pediatric patients with suspected GERD [14].

The most important part of management is counseling. The natural history of GER in infants needs to be explained to parents or care-givers. Other measures are; feeding advice, positioning and feed thickening. Mothers should be instructed to avoid overfeeding, forceful feeding, and to try to give small but frequent feeds. pH studies have shown that reflux is minimal in prone position but the risk of SIDS is maximum in prone position and that’s why prone position is not recommended in infants. However, beyond infancy (>13 months) left lateral position is found to be the best in preventing reflux. Feed thickening by adding rice, corn or potato starch decreases the number regurgitation or vomiting but it does not decreases the acid exposure of esophagus. Hence, feed thickener has only cosmetic value but no therapeutic benefit [22].In a subset of patients (1-10%), regurgitation may be the manifestation of Cow’s milk protein allergy (CMPA) [23]. If there is no response to conventional therapy of counseling, feed thickening in formula-fed infants, a 2 to 4 weeks trial of hypoallergenic milk (extensively hydrolyzed or amino acid formula) is recommended and if the symptoms subside then a challenge and continuation of milk free diet is recommended. However, if there is no response to hypoallergenic formula over 2 to 4 weeks then there is no point in continuing the formula [14].

PPIs are not recommended in this subset of patient as only a few of the infants are likely to have acid-related cause for their symptoms and the largest randomized, controlled trial in infants showed that for symptoms, presumably to be related to reflux disease, a PPI was not better than placebo [24].

Besides medication, life-style modification in terms of weight reduction, avoiding caffeine, chocolate, abstinence from alcohol, tobacco helps in children [14]. Adolescents, like in adults, may benefit from the left lateral decubitus sleeping position with head-end elevation.

Pharmacological therapy

Proton pump inhibitors (PPIs): They are also called Na-K-ATPase inhibitors as they inhibit acid secretion by irreversibly blocking this enzyme in the apical membrane of parietal cells. PPIs should be protected from gastric acid (gets inactivated in acidic media) and that is why preparations are either enteric coated microspheres (mouth dissolving tablets) or capsules. Since they act best in activated parietal cells, PPIs should be taken 30 minutes before breakfast as parietal cells get activated in response to a meal. Once daily dosing is adequate and children (< 10 years) often require a higher per kilogram dose (2-2.5mg/kg/day for omeprazole and 1.4 mg/kg/day for lansoprazole) than adults to obtain a similar degree of acid suppression due to higher metabolism of the drug [23,30,31]. The advantages of PPIs are; more effective in relieving symptoms and healing esophagitis than any other acid suppressants, prolonged action (requires once daily dose), no tachyphylaxis on prolonged use, and relatively safe drug on long term use. Furthermore, due to their strong acid suppression ability, PPIs decrease 24-hour gastric secretion volumes and thereby facilitate gastric emptying [30]. As it takes 2 to 8 days for them to have maximum effect, there is no role of PPIs in on-demand therapy [32,33]. Of the various PPIs (omeprazole, lansoprazole, esomeprazole, rabeprazole, pantoprazole) there is no difference in efficacy of one over the other. Out of all omeprazole, lansoprazole and esomeprazole are FDA approved for pediatric use.

Side effects of different PPIs are almost similar and mild side effects have been reported in up to 14% of children. The most common side effects are headache, diarrhea, constipation and nausea [34,35]. PPIs have been safely used in children for up to 11 years [36].

Prokinetics: There is insufficient evidence to justify the routine use of prokinetics (metoclorpropamide, domperidon or itopride) in the management of GERD [14]. The only situation where prokinetics may be of some use is GERD with associated gastroparesis.

Duration of medical therapy

GERD needs profound acid suppression for a longer duration of time. PPI therapy is recommended for at least 12 weeks and then to taper over 2 to 3 months as rebound hyperacidity is known after sudden stoppage of PPI [37]. In a diagnosed case of GERD, if there is no symptomatic improvement in 4 weeks then the dose of PPI needs to be increased. If there is a relapse on withdrawal of PPI, medication needs to be restarted. Frequent relapses or continuous symptoms are indications for prolonged PPI therapy or surgery. In erosive esophagitis, repeat endoscopy to document healing is indicated at the end of 12 weeks course of PPI therapy, as the risk of relapse is more in those who do not show mucosal healing than those who do. In a long term follow-up study in children, it has been shown that prolonged PPI therapy (median 3 years and up to 12 years) is safe. Regarding the dose of PPI in maintenance therapy, it has been shown that full healing dose is superior to half dose therapy[38].

Nissen fundoplication (open or laparoscopic) may be of benefit in children with confirmed GERD who have failed optimal medical therapy, or who are dependent on medical therapy for a long time, or who are significantly noncompliant to medical therapy, or who have life-threatening complications of GERD. The point to be remember here is that children who need surgery most (neurologically impaired), develop surgery related complications and surgical failure most. Almost two thirds of neurologically impaired children and one thirds of otherwise healthy children develop surgical failure and require long-term medical treatment [1]. Fundoplication in early infancy has a higher failure rate than in late childhood [1, 14].

Bronchial asthma and GERD

The clinical association of bronchial asthma and GERD is very strong but causal relationship between these two entities has not yet been established. Around 30% to 50% of children with persistent, severe asthma have GERD symptoms like heartburn but there is no clinical association of mild, intermittent asthma and GERD [39, 40]. It is not yet clear which one causes what. Is it asthma that causes GERD or is it GERD that causes asthma? Pathophysiologically, either is possible. In asthma, severe cough increases intra-abdominal pressure and decreases intra-thoracic pressure thereby changes the pressure gradient between stomach and esophagus, hyper-inflated lungs alter the relation between crural diaphragm and gastro-esophageal junction, some asthma medicines like beta-agonist decreases LES pressure. All these factors predispose a child with bronchial asthma to reflux. On the other hand, reflux of gastric content can cause bronchospasm by reflux or reflex mechanism. Irritation of esophagus by acid reflux can initiate reflex bronchospasm (reflex theory) as both airway and esophagus share common autonomic nerve supply. Other mechanism is micro-aspiration (reflux theory) of gastric contents which can trigger airway hyper-responsiveness [39].

In a recent multicenter, randomized, placebo-controlled trial from USA in 306 children, it was shown that lansoprazole, in children with poor asthma control who were on inhaled corticosteroid treatment, improved neither symptoms nor lung function but was associated with increased infection [40]. Hence, PPI therapy for poorly controlled asthma without overt GERD is not warranted.

Prevalence of GERD in neurologically impaired children is much higher than in neurologically normal children and the prevalence is almost 50%. Severity and complications of GERD is also much more in this subset of patients. It has been shown that the prevalence of erosive esophagitis is 30% to 70% compared to just 5% in children without neurological defects. This group of children needs prolonged medication and more often surgery [43].

GER is common in infants but GERD is not so common in early childhood. Most infants have physiological reflux and need minimal intervention as their symptoms resolve by 18 months of age. There is no gold standard diagnostic test for GERD and investigations should be tailored to the clinical concern for a given child. Empirical PPI therapy for 4 weeks is justified in older children and adolescents with classical symptoms. For extraesophageal manifestations, pH-metry with or without impedance and for esophagitis, endoscopy is the best investigations. Medical therapy with PPI is very effective and safe. Surgical therapy is not a panacea as it carries significant morbidity and often fails in those who need it most.

Funding: None; Competing interests: None stated.

1. Hassall E. Outcomes of fundoplication: causes for concern,newer options. Arch Dis Child. 2005;90:1047-52.

2. Nelson SP, Chen EH, Syniar GM, Christoffel KK. Prevalence of symptomatic gastroesophageal reflux during infancy. A pediatric practice-based survey, pediatric practice research group. Arch Pediatr Adolesc Med. 1997;151:569-72.

3. Martin AJ, Pratt N, Kennedy D, Ryan P, Ruffin RE, Miles H, et al. Natural history and familial relationships of infant spilling to 9 years of age. Pediatrics. 2002;109:1061-7.

4. Campanozzi A, Bossia G, Pensabene L, Panetta F, Marseglia A, Strisciuglio P, et al. Prevalence and natural history of gastroesophageal reflux: pediatric prospective survey. Pediatrics. 2009;123:779-83.

5. De S, Rajeshwari K, Kalra KK, Gondal R, Malhotra V, Mittal SK. Gastroesophageal reflux in infants and children in north India. Trop Gastroenterol. 2001;22:99-102.

6. Carroll MW, Jacobson K. Gastroesophageal reflux disease in children and adolescents: when and how to treat. Pediatr Drugs. 2012;14:79-89.

7. Nelson P, Chen EH, Syniar GM, Christoffel KK. Prevalence of symptomatic gastroesophageal reflux during childhood: A pediatric practice-based survey, pediatric practice research group. Arch Pediatr Adolesc Med. 2000;154:150-4.

8. Michail S. Gastroesophageal reflux. Pediatr Review. 2007;28:101-3.

9. Tolia V, Vandenplas Y. Systematic review: the extra-esophageal symptoms of gastroesophageal reflux disease in children. Aliment Pharmacol Ther. 2009;29:258-72.

10. Orenstein SR, Shalaby TM, Cohn JF. Reflux symptoms in 100 normal infants: diagnostic validity of the infant gastroesophageal reflux questionnaire. Clin Pediatr. 1996;35:607-14.

11. Hyman PE, Milla PJ, Benninga MA, Davidson GP, Fleisher DF, Taminiau J. Childhood functional gastrointestinal disorders: Neonate/Toddler. Gastroenterology. 2006;130:1519-26.

12. Aggarwal S, Mittal SK, Kalra KK, Rajeshwari K, Gondal R. Infant gastroesophageal reflux disease score: reproducibility and validity in a developing country. Trop Gastroenterol. 2004;25:96-8.

13. Talley NJ, Armstrong D, Junghard O, Wiklund I. Predictors of treatment response in patients with non-erosive reflux disease. Aliment Pharmacol Ther. 2006;24:371-6.

14. Vandenplas Y, Rudolph CD, Di Lornzo C, Hassall E, Liptak G, Muzur L, et al. Pediatric Gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009;49:498-547.

15. Wenzl TG. Role of diagnostic tests in GERD. J Pediatr Gastroenterol Nutr. 2011; 53 (Suppl 2): S4-6.

16. Wenzl TG, Benninga MA, Loots CM, Salvatore S, Vandenplas Y, on behalf of the ESPGHAN EURO-PIG working group. Indications, methodology and interpretation of combined esophageal impedance-pH monitoring in children: ESPGHAN EURO-PIG standard protocol. J Pediatr Gastroenterol Nutr. 2012;55:230-4.

17. Vieira MC, Pisani JC, Mulinari RA. Diagnosis of reflux esophagitis in infants: histology of the distal esophagus must complement upper gastrointestinal endoscopy. J Pediatr. (Rio J) 2004;80:197-202.

18. Boccia G, Manguso F, Miele E, Buonavolonta R, Staiano A. Maintenance therapy of erosive esophagitis in children after healing by omeprazole: is it advisable? Am J Gastroenterol. 2007;102:1291-7.

19. Rudolph CD, Mazur LJ, Liptak GS, Baker RD, Boyle JT, Colletti RB, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children: Recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr. 2001;32:S1-31.

20. Thompson JK, Koehler RE, Richter JE. Detection of gastroesophageal reflux: value of barium studies compared with 24-hr pH monitoring. Am J Roentgenol. 1994;162:621-6.

21. Chen MY, Ott DJ, Sinclair JW, Wu WC, Gelfand DW. Gastroesophageal reflux disease: correlation of esophageal pH testing and radiographic findings. Radiology. 1992;185:483-6.

22. Horvath A, Dziechciarz P, Szajewska H. The effect of thickened-feed interventions on gastroesophageal reflux in infants: systematic review and meta-analysis of randomized, controlled trials. Pediatrics. 2008;122:e1268-77.

23. Cezard JP. Managing gastro-esophageal reflux disease in children. Digestion. 2004;69:3-8.

24. Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr. 2009;154:514-20.

25. Hassall E, Israel D, Shepherd R, Radke M, Dalvag A, Skold B, et al. Omeprazole for treatment of chronic erosive esophagitis in children: a multicenter study of efficacy, safety, tolerability and dose requirements, International Pediatric Omeprazole Study Group. J Pediatr. 2000;137:800-7.

26. Tolia V, Ferry G, Gunasekaran T, Huang B, Keith R, Book L. Efficacy of lansoprazole in the treatment of gastroesophageal reflux disease in children. J Pediatr Gastroenterol Nutr. 2002;35:S308-S318.

27. Sedman A. Aluminum toxicity in childhood. Pediatr Nephrol. 1992;6:383-93.

28. Beall DP, Henslee HB, Webb HR, Scofield RH. Milk-alkali syndrome: a historical review and the description of the modern version of the syndrome. Am J Med Sci. 2006; 331:233-42.

29. Hyman PE, Garvey TQ 3rd, Abrams CE. Tolerance to intravenous ranitidine. J Pediatr. 1987;110:794-6.

30. Israel DM, Hassall E. Omeprazole and other proton pump inhibitors: pharmacology, efficacy, and safety, with special reference to use in children. J Pediatr Gastroenterol Nutr. 1998;27:568-79.

31. Litalien C, Theoret Y, Faure C. Pharmacokinetics of proton pump inhibitors in children. Clin Pharmacokinet. 2005;44:441-66.

32. Savarino V, di Mario F, Scarpignato C. Proton pump inhibitors in GORD: an overview of their pharmacology, efficacy and safety. Pharmacol Res. 2009;59:135-53.

33. Kearns GL, Winter HS. Proton pump inhibitors in pediatrics: relevant pharmacokinetics and pharmacodynamics. J Pediatr Gastroenterol Nutr. 2003;37:S52-9.

34. Zhao J, Li J, Hamer-Maansson JE, Andersson T, Fulmer R, Illueca M,. Pharmacokinetic properties of esomeprazole on children aged 1 to 11 years with symptoms of gastroesophageal reflux disease: a randomized, open-label study. Clin Ther. 2006;28: 1868-76.

35. Li J, Zhao J, Hamer-Maansson JE, Andersson T, Fulmer R, Illueca M, et al. Pharmacokinetic properties of esomeprazole in adolescent patients aged 12 to 17 years with symptoms of gastroesophageal reflux disease: a randomized, open-label study. Clin Ther. 2006;28:419-27.

36. Hassall E, Kerr W, El-Serag HB. Characteristics of children receiving proton pump inhibitors continuously for up to 11 years duration. J Pediatr. 2007;150:262-7, 267.e1

37. Fossmark R, Johnsen G, Johanessen E, Waldum HL. Rebound acid hyper secretion after long-term inhibition of gastric acid secretion. Aliment Pharmacol Ther. 2005;21:149-54.

38. Illueca M, Wernersson B, Henderson C, Lundborg P. Maintenance treatment with proton pump inhibitors for reflux esophagitis in pediatric patients: a systematic literature analysis. J Pediatr Gastroenterol Nutr. 2010;51:733-40.

39. Gold BD.Asthma and gastroesophageal reflux disease in children: exploring the relationship. J Pediatr. 2005;146: S13-S20.

40. Writing committee for the American Lung Association Asthma Clinical Research Centers, Holbrook JT, Wise RA, Gold BD, Blake K, Brown ED, et al. Lansoprazole for children with poorly controlled asthma. JAMA. 2012;307:373-81.

41. Khoshoo V, Haydel R Jr. Effect of antireflux treatment on asthma exacerbation in nonatopic children. J Pediatr Gastroenterol Nutr. 2007;44:331-5.

42. Stordal K, Johannesdottir GB, Bentsen BS, Knudsen PK, Carlsen KC, Closs O, et al. Acid suppression does not change respiratory symptoms in children with asthma and gastro-esophageal reflux disease. Arch Dis Child. 2005;90:956-60.