Gastroesophageal Reflux and Respiratory Tract Symptoms

  • Daniel R. Duncan
  • Rachel L. RosenEmail author


Gastroesophageal reflux has been held responsible for a variety of respiratory symptoms including asthma, recurrent pneumonia, and myriad upper airway symptoms in the pediatric population. The focus of much of the early research has been on proving the association between esophageal reflux events and extraesophageal symptoms though recent studies have explored the role of biomarkers as novel diagnostic tests. Because of the lack of sensitive diagnostic tests for extraesophageal reflux disease, many clinicians continue to prescribe or recommend empiric medical and surgical reflux therapies though there is again a lack of convincing data showing benefit to these therapies and some studies even suggesting harm. The field of reflux-related respiratory disorders continues to evolve, however, and the challenge of caring for these pediatric patients requires a multidisciplinary team-based approach.


Gastroesophageal reflux disease Extraesophageal reflux Reactive airway disease Asthma Recurrent pneumonia Upper airway symptoms Multichannel impedance with pH Pepsin Microbiome Proton pump inhibitor Fundoplication 


  1. 1.
    Orenstein SR, Orenstein DM. Gastroesophageal reflux and respiratory disease in children. J Pediatr. 1988;112(6):847–58.PubMedCrossRefGoogle Scholar
  2. 2.
    Lasser MS, Liao JG, Burd RS. National trends in the use of antireflux procedures for children. Pediatrics. 2006;118(5):1828–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Francis DO, Rymer JA, Slaughter JC, Choksi Y, Jiramongkolchai P, Ogbeide E, et al. High economic burden of caring for patients with suspected extraesophageal reflux. Am J Gastroenterol. 2013;108(6):905–11.PubMedCrossRefGoogle Scholar
  4. 4.
    Collaco JM, Aherrera AD, Au Yeung KJ, Lefton-Greif MA, Hoch J, Skinner ML. Interdisciplinary pediatric aerodigestive care and reduction in health care costs and burden. JAMA Otolaryngol Head Neck Surg. 2015;141(2):101–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Tolia V, Vandenplas Y. Systematic review: the extra-oesophageal symptoms of gastro-oesophageal reflux disease in children. Aliment Pharmacol Ther. 2009;29(3):258–72.PubMedCrossRefGoogle Scholar
  6. 6.
    Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux disease and asthma: a systematic review. Gut. 2007;56(12):1654–64.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Gislason T, Janson C, Vermeire P, Plaschke P, Bjornsson E, Gislason D, et al. Respiratory symptoms and nocturnal gastroesophageal reflux: a population-based study of young adults in three European countries. Chest. 2002;121(1):158–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Lightdale JR, Gremse DA. Gastroesophageal reflux: management guidance for the pediatrician. Pediatrics. 2013;131(5):e1684–95.PubMedCrossRefGoogle Scholar
  9. 9.
    Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn C, Redd SC. Surveillance for asthma--United States, 1980–1999. MMWR Surveil summ. 2002;51(1):1–13.Google Scholar
  10. 10.
    Potter PC. Current guidelines for the management of asthma in young children. Allergy Asthma Immunol Res. 2010;2(1):1–13.PubMedCrossRefGoogle Scholar
  11. 11.
    Gold BD. Asthma and gastroesophageal reflux disease in children: exploring the relationship. J Pediatr. 2005;146(3, Supplement):S13–20.PubMedCrossRefGoogle Scholar
  12. 12.
    Thakkar K, Boatright RO, Gilger MA, El-Serag HB. Gastroesophageal reflux and asthma in children: a systematic review. Pediatrics. 2010;125(4):e925–30.PubMedCrossRefGoogle Scholar
  13. 13.
    Debley JS, Redding GJ, Critchlow CW. Impact of adolescence and gender on asthma hospitalization: a population-based birth cohort study. Pediatr Pulmonol. 2004;38(6):443–50.PubMedCrossRefGoogle Scholar
  14. 14.
    Ravelli AM, Panarotto MB, Verdoni L, Consolati V, Bolognini S. Pulmonary aspiration shown by scintigraphy in gastroesophageal reflux-related respiratory disease. Chest. 2006;130(5):1520–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Starosta V, Kitz R, Hartl D, Marcos V, Reinhardt D, Griese M. Bronchoalveolar pepsin, bile acids, oxidation, and inflammation in children with gastroesophageal reflux disease. Chest. 2007;132(5):1557–64.PubMedCrossRefGoogle Scholar
  16. 16.
    Gopalareddy V, He Z, Soundar S, Bolling L, Shah M, Penfil S, et al. Assessment of the prevalence of microaspiration by gastric pepsin in the airway of ventilated children. Acta Paediatr. 2008;97(1):55–60.PubMedCrossRefGoogle Scholar
  17. 17.
    Lee AL, Button BM, Denehy L, Roberts S, Bamford T, FT M, et al. Exhaled breath condensate pepsin: potential noninvasive test for gastroesophageal reflux in COPD and bronchiectasis. Respir Care. 2015;60(2):244–50.PubMedCrossRefGoogle Scholar
  18. 18.
    Banaszkiewicz A, Dembinski L, Zawadzka-Krajewska A, Dziekiewicz M, Albrecht P, Kulus M, et al. Evaluation of laryngopharyngeal reflux in pediatric patients with asthma using a new technique of pharyngeal pH-monitoring. Adv Exp Med Biol. 2013;755:89–95.PubMedCrossRefGoogle Scholar
  19. 19.
    Kilic M, Ozturk F, Kirmemis O, Atmaca S, Guner SN, Caltepe G, et al. Impact of laryngopharyngeal and gastroesophageal reflux on asthma control in children. Int J Pediatr Otorhinolaryngol. 2013;77(3):341–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Condino AA, Sondheimer J, Pan Z, Gralla J, Perry D, O'Connor JA. Evaluation of gastroesophageal reflux in pediatric patients with asthma using impedance-pH monitoring. J Pediatr. 2006;149(2):216–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Chang AB, Connor FL, Petsky HL, Eastburn MM, Lewindon PJ, Hall C, et al. An objective study of acid reflux and cough in children using an ambulatory pHmetry-cough logger. Arch Dis Child. 2011;96(5):468–72.PubMedCrossRefGoogle Scholar
  22. 22.
    Molle LD, Goldani HA, Fagondes SC, Vieira VG, Barros SG, Silva PS, et al. Nocturnal reflux in children and adolescents with persistent asthma and gastroesophageal reflux. J Asthma. 2009;46(4):347–50.PubMedCrossRefGoogle Scholar
  23. 23.
    Holbrook JT, Wise RA, Gold BD, Blake K, Brown ED, Castro M, et al. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA. 2012;307(4):373–81.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Khoshoo V, Haydel R Jr. Effect of antireflux treatment on asthma exacerbations in nonatopic children. J Pediatr Gastroenterol Nutr. 2007;44(3):331–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Sopo SM, Radzik D, Calvani M. Does treatment with proton pump inhibitors for gastroesophageal reflux disease (GERD) improve asthma symptoms in children with asthma and GERD? a systematic review. J Investig Allergol Clin Immunol. 2009;19(1):1–5.PubMedGoogle Scholar
  26. 26.
    Lee AL, Goldstein RS. Gastroesophageal reflux disease in COPD: links and risks. Int J Chron Obstruct Pulmon Dis. 2015;10:1935–49.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Gadel AA, Mostafa M, Younis A, Haleem M. Esophageal motility pattern and gastro-esophageal reflux in chronic obstructive pulmonary disease. Hepato-Gastroenterology. 2012;59(120):2498–502.PubMedGoogle Scholar
  28. 28.
    Sontag SJ, O’Connell S, Khandelwal S, Miller T, Nemchausky B, Schnell TG, et al. Effect of positions, eating, and bronchodilators on gastroesophageal reflux in asthmatics. Dig Dis Sci. 1990;35(7):849–56.PubMedCrossRefGoogle Scholar
  29. 29.
    Lazenby JP, Guzzo MR, Harding SM, Patterson PE, Johnson LF, Bradley LA. Oral corticosteroids increase esophageal acid contact times in patients with stable asthma. Chest. 2002;121(2):625–34.PubMedCrossRefGoogle Scholar
  30. 30.
    Berquist WE, Rachelefsky GS, Rowshan N, Siegel S, Katz R, Welch M. Quantitative gastroesophageal reflux and pulmonary function in asthmatic children and normal adults receiving placebo, theophylline, and metaproterenol sulfate therapy. J Allergy Clin Immunol. 1984;73(2):253–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Berquist WE, Rachelefsky GS, Kadden M, Siegel SC, Katz RM, Mickey MR, et al. Effect of theophylline on gastroesophageal reflux in normal adults. J Allergy Clin Immunol. 1981;67(5):407–11.PubMedCrossRefGoogle Scholar
  32. 32.
    Danus O, Casar C, Larrain A, Pope CE 2nd. Esophageal reflux--an unrecognized cause of recurrent obstructive bronchitis in children. J Pediatr. 1976;89(2):220–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Barnhart DC, Hall M, Mahant S, Goldin AB, Berry JG, Faix RG, et al. Effectiveness of fundoplication at the time of gastrostomy in infants with neurological impairment. JAMA Pediatr. 2013;167(10):911–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Lee SL, Shabatian H, Hsu JW, Applebaum H, Haigh PI. Hospital admissions for respiratory symptoms and failure to thrive before and after Nissen fundoplication. J Pediatr Surg. 2008;43(1):59–63. discussion -5PubMedCrossRefGoogle Scholar
  35. 35.
    Wong KK, Liu XL. Perioperative and late outcomes of laparoscopic fundoplication for neurologically impaired children with gastro-esophageal reflux disease. Chin Med J. 2012;125(21):3905–8.PubMedGoogle Scholar
  36. 36.
    Livingston MH, Shawyer AC, Rosenbaum PL, Jones SA, Walton JM. Fundoplication and gastrostomy versus percutaneous gastrojejunostomy for gastroesophageal reflux in children with neurologic impairment: a systematic review and meta-analysis. J Pediatr Surg. 2015;50(5):707–14.PubMedCrossRefGoogle Scholar
  37. 37.
    Duncan DR, Amirault J, Johnston N, Mitchell P, Larson K, Rosen RL. gastroesophageal reflux burden, even in children that aspirate, does not increase pediatric hospitalization. J Pediatr Gastroenterol Nutr. 2016;63(2):210–7.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur 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(4):498–547.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Rosbe KW, Kenna MA, Auerbach AD. Extraesophageal reflux in pediatric patients with upper respiratory symptoms. Arch Otolaryngol Head Neck Surg. 2003;129(11):1213–20.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Johnston N, Ondrey F, Rosen R, Hurley BP, Gould J, Allen J, et al. Airway reflux. Ann N Y Acad Sci. 2016;1381:5–13.PubMedCrossRefGoogle Scholar
  41. 41.
    Rosen R, Mitchell PD, Amirault J, Amin M, Watters K, Rahbar R. The edematous and erythematous airway does not denote pathological gastroesophageal reflux. J Peds. 2017;183:127–31.CrossRefGoogle Scholar
  42. 42.
    Dziekiewicz MA, Banaszkiewicz A, Urzykowska A, Lisowska A, Rachel M, Sands D, et al. Gastroesophageal reflux disease in children with cystic fibrosis. Adv Exp Med Biol. 2015;873:1–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Woodley FW, Machado RS, Hayes D Jr, Di Lorenzo C, Kaul A, Skaggs B, et al. Children with cystic fibrosis have prolonged chemical clearance of acid reflux compared to symptomatic children without cystic fibrosis. Dig Dis Sci. 2014;59(3):623–30.PubMedCrossRefGoogle Scholar
  44. 44.
    van der Doef HP, Arets HG, Froeling SP, Westers P, Houwen RH. Gastric acid inhibition for fat malabsorption or gastroesophageal reflux disease in cystic fibrosis: longitudinal effect on bacterial colonization and pulmonary function. J Pediatr. 2009;155(5):629–33.PubMedCrossRefGoogle Scholar
  45. 45.
    Doumit M, Krishnan U, Jaffe A, Belessis Y. Acid and non-acid reflux during physiotherapy in young children with cystic fibrosis. Pediatr Pulmonol. 2012;47(2):119–24.PubMedCrossRefGoogle Scholar
  46. 46.
    Button BM, Heine RG, Catto-Smith AG, Phelan PD, Olinsky A. Chest physiotherapy, gastro-oesophageal reflux, and arousal in infants with cystic fibrosis. Arch Dis Child. 2004;89(5):435–9.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Button BM, Roberts S, Kotsimbos TC, Levvey BJ, Williams TJ, Bailey M, et al. Gastroesophageal reflux (symptomatic and silent): a potentially significant problem in patients with cystic fibrosis before and after lung transplantation. J Heart Lung Transplant. 2005;24(10):1522–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Palm K, Sawicki G, Rosen R. The impact of reflux burden on Pseudomonas positivity in children with Cystic Fibrosis. Pediatr Pulmonol. 2011;47:582–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Boesch RP, Acton JD. Outcomes of fundoplication in children with cystic fibrosis. J Pediatr Surg. 2007;42(8):1341–4.PubMedCrossRefGoogle Scholar
  50. 50.
    Pegna V, Mickevicius A, Tsang C. How useful is antireflux surgery in lung transplant patients with gastroesophageal reflux? Medicina. 2014;50(6):318–22.PubMedCrossRefGoogle Scholar
  51. 51.
    Dy FJ, Freiberger D, Liu E, Boyer D, Visner G, Rosen R. The impact of gastroesophageal reflux and delayed gastric emptying on pediatric lung transplant outcomes. J Heart Lung Transplant. 2017; doi: 10.1016/j.healun.2017.01.005.
  52. 52.
    Rosen R, Nurko S. The importance of multichannel intraluminal impedance in the evaluation of children with persistent respiratory symptoms. Am J Gastroenterol. 2004;99(12):2452–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Ghezzi M, Guida E, Ullmann N, Sacco O, Mattioli G, Jasonni V, et al. Weakly acidic gastroesophageal refluxes are frequently triggers in young children with chronic cough. Pediatr Pulmonol. 2012;48:295–302.PubMedCrossRefGoogle Scholar
  54. 54.
    Rosen R, Amirault J, Johnston N, Haver K, Khatwa U, Rubinstein E, et al. The utility of endoscopy and multichannel intraluminal impedance testing in children with cough and wheezing. Pediatr Pulmonol. 2013;49:1090–6.PubMedCrossRefGoogle Scholar
  55. 55.
    Jadcherla SR, Gupta A, Fernandez S, Nelin LD, Castile R, Gest AL, et al. Spatiotemporal characteristics of acid refluxate and relationship to symptoms in premature and term infants with chronic lung disease. Am J Gastroenterol. 2008;103(3):720–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Borrelli O, Battaglia M, Galos F, Aloi M, De Angelis D, Moretti C, et al. Non-acid gastro-oesophageal reflux in children with suspected pulmonary aspiration. Dig Liver Dis. 2010;42(2):115–21.PubMedCrossRefGoogle Scholar
  57. 57.
    Rosen R, Johnston N, Hart K, Khatwa U, Katz E, Nurko S. Higher rate of bronchoalveolar lavage culture positivity in children with nonacid reflux and respiratory disorders. J Pediatr. 2011;159(3):504–6.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Mousa H, Woodley FW, Metheney M, Hayes J. Testing the association between gastroesophageal reflux and apnea in infants. J Pediatr Gastroenterol Nutr. 2005;41(2):169–77.PubMedCrossRefGoogle Scholar
  59. 59.
    Zimbric G, Bonkowsky JL, Jackson WD, Maloney CG, Srivastava R. Adverse outcomes associated with gastroesophageal reflux disease are rare following an apparent life-threatening event. J Hosp Med. 2012;7(6):476–81.PubMedCrossRefGoogle Scholar
  60. 60.
    Mittal MK, Donda K, Baren JM. Role of pneumography and esophageal pH monitoring in the evaluation of infants with apparent life-threatening event: a prospective observational study. Clin Pediatr. 2013;52(4):338–43.CrossRefGoogle Scholar
  61. 61.
    McMurray JS, Gerber M, Stern Y, Walner D, Rudolph C, Willging JP, et al. Role of laryngoscopy, dual pH probe monitoring, and laryngeal mucosal biopsy in the diagnosis of pharyngoesophageal reflux. Ann Otol Rhinol Laryngol. 2001;110(4):299–304.PubMedCrossRefGoogle Scholar
  62. 62.
    Sifrim D, Dupont L, Blondeau K, Zhang X, Tack J, Janssens J. Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring. Gut. 2005;54(4):449–54.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Blondeau K, Mertens V, Dupont L, Pauwels A, Farre R, Malfroot A, et al. The relationship between gastroesophageal reflux and cough in children with chronic unexplained cough using combined impedance-pH-manometry recordings. Pediatr Pulmonol. 2011;46(3):286–94.PubMedCrossRefGoogle Scholar
  64. 64.
    Rosen R, Amirault J, Giligan E, Khatwa U, Nurko S. Intraesophageal pressure recording improves the detection of cough during multichannel intraluminal impedance testing in children. J Pediatr Gastroenterol Nutr. 2014;58(1):22–6.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Belafsky PC, Postma GN, Koufman JA. The validity and reliability of the reflux finding score (RFS). Laryngoscope. 2001;111(8):1313–7.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    van der Pol RJ, Singendonk MM, Konig AM, Hoeve H, Kammeijer Q, Pullens B, et al. Development of the reflux finding score for infants and its observer agreement. J Pediatr. 2014;165(3):479–84.PubMedCrossRefGoogle Scholar
  67. 67.
    Yuksel ES, Slaughter JC, Mukhtar N, Ochieng M, Sun G, Goutte M, et al. An oropharyngeal pH monitoring device to evaluate patients with chronic laryngitis. Neurogastroenterol Motil. 2013;25(5):e315–23.PubMedCrossRefGoogle Scholar
  68. 68.
    Andrews TM, Orobello N. Histologic versus pH probe results in pediatric laryngopharyngeal reflux. Int J Pediatr Otorhinolaryngol. 2013;77(5):813–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Chiou E, Rosen R, Jiang H, Nurko S. Diagnosis of supra-esophageal gastric reflux: correlation of oropharyngeal pH with esophageal impedance monitoring for gastro-esophageal reflux. Neurogastroenterol Motil. 2011;23(8):717–e326.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Ummarino D, Vandermeulen L, Roosens B, Urbain D, Hauser B, Vandenplas Y. Gastroesophageal reflux evaluation in patients affected by chronic cough: restech versus multichannel intraluminal impedance/pH metry. Laryngoscope. 2013;123(4):980–4.PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Patel DA, Harb AH, Vaezi MF. Oropharyngeal reflux monitoring and atypical gastroesophageal reflux disease. Curr Gastroenterol Rep. 2016;18(3):12.PubMedCrossRefGoogle Scholar
  72. 72.
    Rosen R, Rodriguez L, Nurko S. Pediatric rumination subtypes: a study using high resolution esophageal manometry with impedance. Neurogastroenterol Motil. 2016;29:e12998.CrossRefGoogle Scholar
  73. 73.
    Singendonk MM, Smits MJ, Heijting IE, van Wijk MP, Nurko S, Rosen R, et al. Inter- and intrarater reliability of the Chicago Classification in pediatric high-resolution esophageal manometry recordings. Neurogastroenterol Motil. 2015;27(2):269–76.PubMedCrossRefGoogle Scholar
  74. 74.
    Rommel N, Omari TI, Selleslagh M, Kritas S, Cock C, Rosan R, et al. High-resolution manometry combined with impedance measurements discriminates the cause of dysphagia in children. Eur J Pediatr. 2015;174(12):1629–37.PubMedCrossRefGoogle Scholar
  75. 75.
    Rosen R, Fritz J, Nurko A, Simon D, Nurko S. Lipid-laden macrophage index is not an indicator of gastroesophageal reflux-related respiratory disease in children. Pediatrics. 2008;121(4):e879–84.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Krishnan U, Mitchell JD, Tobias V, Day AS, Bohane TD. Fat laden macrophages in tracheal aspirates as a marker of reflux aspiration: a negative report. J Pediatr Gastroenterol Nutr. 2002;35(3):309–13.PubMedCrossRefGoogle Scholar
  77. 77.
    Mertens V, Blondeau K, Van Oudenhove L, Vanaudenaerde B, Vos R, Farre R, et al. Bile acids aspiration reduces survival in lung transplant recipients with BOS despite azithromycin. Am J Transplant. 2011;11(2):329–35.PubMedCrossRefGoogle Scholar
  78. 78.
    De Luca D, Minucci A, Zecca E, Piastra M, Pietrini D, Carnielli VP, et al. Bile acids cause secretory phospholipase A2 activity enhancement, revertible by exogenous surfactant administration. Intensive Care Med. 2009;35(2):321–6.PubMedCrossRefGoogle Scholar
  79. 79.
    Krishnan U, Mitchell JD, Messina I, Day AS, Bohane TD. Assay of tracheal pepsin as a marker of reflux aspiration. J Pediatr Gastroenterol Nutr. 2002;35(3):303–8.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Meert KL, Daphtary KM, Metheny NA. Detection of pepsin and glucose in tracheal secretions as indicators of aspiration in mechanically ventilated children. Pediatr Crit Care Med. 2002;3(1):19–22.PubMedCrossRefGoogle Scholar
  81. 81.
    Abdallah AF, El-Desoky T, Fathi K, Elkashef WF, Zaki A. Clinical utility of bronchoalveolar lavage pepsin in diagnosis of gastroesophageal reflux among wheezy infants. Can Respir J. 2016;2016:9480843.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Fortunato JE, D’Agostino RB Jr, Lively MO. Pepsin in saliva as a biomarker for oropharyngeal reflux compared with 24-hour esophageal impedance/pH monitoring in pediatric patients. Neurogastroenterol Motil. 2016;29:e12936.CrossRefGoogle Scholar
  83. 83.
    Dy F, Amirault J, Mitchell PD, Rosen R. Salivary pepsin lacks sensitivity as a diagnostic tool to evaluate extraesophageal reflux disease. J Pediatr. 2016;177:53–8.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Rosen R, Johnston N, Hart K, Khatwa U, Nurko S. The presence of pepsin in the lung and its relationship to pathologic gastro-esophageal reflux. Neurogastroenterol Motil. 2012;24(2):129–e85.PubMedCrossRefGoogle Scholar
  85. 85.
    Farrell S, McMaster C, Gibson D, Shields MD, McCallion WA. Pepsin in bronchoalveolar lavage fluid: a specific and sensitive method of diagnosing gastro-oesophageal reflux-related pulmonary aspiration. J Pediatr Surg. 2006;41(2):289–93.PubMedCrossRefGoogle Scholar
  86. 86.
    Schallom M, Tricomi SM, Chang YH, Metheny NA. A pilot study of pepsin in tracheal and oral secretions. Am J Crit Care. 2013;22(5):408–11.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Emilsson OI, Benediktsdottir B, Olafsson I, Cook E, Juliusson S, Bjornsson ES, et al. Respiratory symptoms, sleep-disordered breathing and biomarkers in nocturnal gastroesophageal reflux. Respir Res. 2016;17(1):115.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Hunt J, Yu Y, Burns J, Gaston B, Ngamtrakulpanit L, Bunyan D, et al. Identification of acid reflux cough using serial assays of exhaled breath condensate pH. Cough. 2006;2:3.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Fitzpatrick AM, Holbrook JT, Wei CY, Brown MS, Wise RA, Teague WG. Exhaled breath condensate pH does not discriminate asymptomatic gastroesophageal reflux or the response to lansoprazole treatment in children with poorly controlled asthma. J Allergy Clin Immunol Pract. 2014;2(5):579–86.e7.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Canani RB, Cirillo P, Roggero P, Romano C, Malamisura B, Terrin G, et al. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006;117(5):e817–20.PubMedCrossRefGoogle Scholar
  91. 91.
    Terrin G, Passariello A, De Curtis M, Manguso F, Salvia G, Lega L, et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics. 2012;129(1):e40–5.PubMedCrossRefGoogle Scholar
  92. 92.
    Rosen R. Gastroesophageal reflux in infants: more than just a pHenomenon. JAMA Pediatr. 2014;168(1):83–9.PubMedCrossRefGoogle Scholar
  93. 93.
    Garland JS, Alex CP, Johnston N, Yan JC, Werlin SL. Association between tracheal pepsin, a reliable marker of gastric aspiration, and head of bed elevation among ventilated neonates. J Neonatal-Perinatal Med. 2014;7(3):185–92.PubMedGoogle Scholar
  94. 94.
    Nikaki K, Woodland P, Sifrim D. Adult and paediatric GERD: diagnosis, phenotypes and avoidance of excess treatments. Nat Rev Gastroenterol Hepatol. 2016;13(9):529–42.PubMedCrossRefGoogle Scholar
  95. 95.
    Garrigues V, Gisbert L, Bastida G, Ortiz V, Bau I, Nos P, et al. Manifestations of gastroesophageal reflux and response to omeprazole therapy in patients with chronic posterior laryngitis: an evaluation based on clinical practice. Dig Dis Sci. 2003;48(11):2117–23.PubMedCrossRefGoogle Scholar
  96. 96.
    Wo JM, Grist WJ, Gussack G, Delgaudio JM, Waring JP. Empiric trial of high-dose omeprazole in patients with posterior laryngitis: a prospective study. Am J Gastroenterol. 1997;92(12):2160–5.PubMedGoogle Scholar
  97. 97.
    Fass R, Noelck N, Willis MR, Navarro-Rodriguez T, Wilson K, Powers J, et al. The effect of esomeprazole 20 mg twice daily on acoustic and perception parameters of the voice in laryngopharyngeal reflux. Neurogastroenterol Motil. 2010;22(2):134–41. e44-5PubMedCrossRefGoogle Scholar
  98. 98.
    Vaezi MF, Richter JE, Stasney CR, Spiegel JR, Iannuzzi RA, Crawley JA, et al. Treatment of chronic posterior laryngitis with esomeprazole. Laryngoscope. 2006;116(2):254–60.PubMedCrossRefGoogle Scholar
  99. 99.
    Faruqi S, Molyneux ID, Fathi H, Wright C, Thompson R, Morice AH. Chronic cough and esomeprazole: a double-blind placebo-controlled parallel study. Respirology. 2011;16(7):1150–6.PubMedCrossRefGoogle Scholar
  100. 100.
    Shaheen NJ, Crockett SD, Bright SD, Madanick RD, Buckmire R, Couch M, et al. Randomised clinical trial: high-dose acid suppression for chronic cough - a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2011;33(2):225–34.PubMedCrossRefGoogle Scholar
  101. 101.
    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-oesophageal reflux disease. Arch Dis Child. 2005;90(9):956–60.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr. 2009;154(4):514–20. e4PubMedCrossRefGoogle Scholar
  103. 103.
    Vandenplas Y. Management of paediatric GERD. Nat Rev Gastroenterol Hepatol. 2014;11(3):147–57.PubMedCrossRefGoogle Scholar
  104. 104.
    Kastelik JA, Redington AE, Aziz I, Buckton GK, Smith CM, Dakkak M, et al. Abnormal oesophageal motility in patients with chronic cough. Thorax. 2003;58(8):699–702.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Ou XM, Feng YL, Wen FQ, Wang K, Yang J, Deng ZP, et al. Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-kappaB. Respirology. 2008;13(1):63–72.CrossRefGoogle Scholar
  106. 106.
    Mertens V, Blondeau K, Pauwels A, Farre R, Vanaudenaerde B, Vos R, et al. Azithromycin reduces gastroesophageal reflux and aspiration in lung transplant recipients. Dig Dis Sci. 2009;54(5):972–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Solidoro P, Braido F, Boffini M, Corsico AG. New life for macrolides. Minerva Med. 2013;104(6 Suppl 1):7–14.PubMedGoogle Scholar
  108. 108.
    Rosen R, Amirault J, Liu H, Mitchell P, Hu L, Khatwa U, et al. Changes in gastric and lung microflora with Acid suppression: Acid suppression and bacterial growth. JAMA Pediatr. 2014;168(10):932–7.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Goldin AB, Garrison M, Christakis D. Variations between hospitals in antireflux procedures in children. Arch Pediatr Adolesc Med. 2009;163(7):658–63.PubMedCrossRefGoogle Scholar
  110. 110.
    Tannuri AC, Tannuri U, Mathias AL, Velhote MC, Romao RL, Goncalves ME, et al. Gastroesophageal reflux disease in children: efficacy of Nissen fundoplication in treating digestive and respiratory symptoms. Experience of a single center. Dis Esophagus. 2008;21(8):746–50.PubMedCrossRefGoogle Scholar
  111. 111.
    Frongia G, Ahrens P, Capobianco I, Kossler-Ebs J, Stroh T, Fritsche R, et al. Long-term effects of fundoplication in children with chronic airway diseases. J Pediatr Surg. 2015;50(1):206–10.PubMedCrossRefGoogle Scholar
  112. 112.
    Lee SL. Short- and long-term antireflux and asthma medication use in children after nissen fundoplication. Perm J. 2009;13(2):4–11.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Goldin AB, Sawin R, Seidel KD, Flum DR. Do antireflux operations decrease the rate of reflux-related hospitalizations in children? Pediatrics. 2006;118(6):2326–33.PubMedCrossRefGoogle Scholar
  114. 114.
    Richards CA, Milla PJ, Andrews PL, Spitz L. Retching and vomiting in neurologically impaired children after fundoplication: predictive preoperative factors. J Pediatr Surg. 2001;36(9):1401–4.PubMedCrossRefGoogle Scholar
  115. 115.
    Spiegel B. Diagnostic testing in extraesophageal GERD: another case of "furor medicus"? Am J Gastroenterol. 2013;108(6):912–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Aerodigestive Center, Center for Motility and Functional Gastrointestinal Disorders, Division of GastroenterologyHepatology and Nutrition, Boston Children’s HospitalBostonUSA

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