Journal of Gastrointestinal Surgery

, Volume 17, Issue 8, pp 1526–1535

The Pulmonary Side of Reflux Disease: from Heartburn to Lung Fibrosis

  • Marco E. Allaix
  • P. Marco Fisichella
  • Imre Noth
  • Bernardino M. Mendez
  • Marco G. Patti
Review Article

Abstract

Introduction

Gastroesophageal reflux disease (GERD) is the most prevalent gastrointestinal disorder in the USA. Heartburn is the symptom most commonly associated with this disease, and the highly commercialized medical treatment directed toward relief of this symptom represents a 10-billion-dollar-per-year industry.

Discussion

Unfortunately, there is often little awareness that GERD can be potentially a lethal disease as it can cause esophageal cancer. Furthermore, there is even less awareness about the relationship between GERD and respiratory disorders with the potential for severe morbidity and even mortality.

Keywords

Gastroesophageal reflux disease Lower esophageal sphincter Esophageal peristalsis Hiatal hernia Obesity Esophageal manometry Ambulatory pH monitoring Idiopathic pulmonary fibrosis Lung transplantation Laparoscopic Nissen fundoplication 

References

  1. 1.
    Shaheen NJ, Hansen RA, Morgan DR, Gangarosa LM, Ringel Y, Thiny MT, Russo MW, Sandler RS. The burden of gastrointestinal and liver diseases, 2006. Am J Gastroenterol 2006;101:2128–2138.PubMedCrossRefGoogle Scholar
  2. 2.
    Patti MG, Diener U, Tamburini A, Molena D, Way LW. Role of esophageal function tests in diagnosis of gastroesophageal reflux disease. Dig Dis Sci 2001;46:597–602.PubMedCrossRefGoogle Scholar
  3. 3.
    von Rahden BH, Scheurlen M, Filser J, Stein HJ, Germer CT. Newly recognized side-effects of proton pump inhibitors. Arguments in favor of fundoplication for GERD? Chirurg. 2012;83:38–44.CrossRefGoogle Scholar
  4. 4.
    Wheeler JB, Reed CE. Epidemiology of esophageal cancer. Surg. Clin. N. Am. 2012;92:1077–1087.PubMedCrossRefGoogle Scholar
  5. 5.
    Pohl H, Wrobel K, Bojarski C, Voderholzer W, Sonnenberg A, Rösch T, Baumgart DC. Risk factors in the development of esophageal adenocarcinoma. Am J Gastroenterol 2012;108:200–207.PubMedCrossRefGoogle Scholar
  6. 6.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10–29.PubMedCrossRefGoogle Scholar
  7. 7.
    Lee JS, Collard HR, Raghu G, Sweet MP, Hays SR, Campos GM, Golden JA, King TE Jr. Does chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med 2010;123:304–311.PubMedCrossRefGoogle Scholar
  8. 8.
    Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006;174:810–816.PubMedCrossRefGoogle Scholar
  9. 9.
    Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr; Idiopathic Pulmonary Fibrosis Study Group. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Eng. J Med 2004;350:125–133.CrossRefGoogle Scholar
  10. 10.
    Patti MG, Tedesco P, Golden J, Hays S, Hoopes C, Meneghetti A, Damani T, Way LW. Idiopathic pulmonary fibrosis: how often is it really idiopathic? J Gastrointest Surg 2005;9:1053–1056.PubMedCrossRefGoogle Scholar
  11. 11.
    Sweet MP, Patti MG, Leard LE, Golden JA, Hays SR, Hoopes C, Theodore PR. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg 2007;133:1078–1084.PubMedCrossRefGoogle Scholar
  12. 12.
    Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy? Eur Respir J. 2012;39:242–245.PubMedCrossRefGoogle Scholar
  13. 13.
    Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900–1920.PubMedCrossRefGoogle Scholar
  14. 14.
    Moraes-Filho J, Cecconello I, Gama-Rodrigues J, Castro L, Henry MA, Meneghelli UG, Quigley E; Brazilian Consensus Group. Brazilian consensus on gastroesophageal reflux disease: proposals for assessment, classification, and management. Am J Gastroenterol 2002;97:241–248.PubMedCrossRefGoogle Scholar
  15. 15.
    Zaninotto G, DeMeester TR, Schwizer W, Johansson KE, Chang SC. The lower esophageal sphincter in health and disease. Am J Surg 1988;155:104–111.PubMedCrossRefGoogle Scholar
  16. 16.
    Holloway RH, Penagini R, Ireland AC. Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol Gastrointest Liver Physiol 1995;268:G128-G133.Google Scholar
  17. 17.
    Mittal RK, Holloway RH, Penagini R, Blackshaw LA, Dent J. Transient lower esophageal sphincter relaxation. Gastroenterology 1995;109:601–610.PubMedCrossRefGoogle Scholar
  18. 18.
    Patti MG, Goldberg HI, Arcerito M, Bortolasi L, Tong J, Way LW. Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of mucosal injury. Am J Surg 1996;171:182–186.PubMedCrossRefGoogle Scholar
  19. 19.
    Jones MP, Sloan SS, Rabine JC, Ebert CC, Huang CF, Kahrilas PJ. Hiatal hernia size is the dominant determinant of esophagitis presence and severity in gastroesophageal reflux disease. Gastroenterol 2001;96:1711–1717.Google Scholar
  20. 20.
    Ayazi S, DeMeester SR, Hsieh CC, Zehetner J, Sharma G, Grant KS, Oh DS, Lipham JC, Hagen JA, DeMeester TR. Thoraco-abdominal pressure gradients during the phases of respiration contribute to gastroesophageal reflux disease. Dig Dis Sci 2011;56:1718–1722.PubMedCrossRefGoogle Scholar
  21. 21.
    Casanova C, Baudet JS, del Valle Velasco M, Martin JM, Aguirre-Jaime A, de Torres JP, Celli BR. Increased gastro-oesophageal reflux disease in patients with severe COPD. Eur Respir J 2004;23:841–845.PubMedCrossRefGoogle Scholar
  22. 22.
    Herbella FAM, Sweet MP, Tedesco P, Nipomnick I, Patti MG. Gastroesophageal reflux disease and obesity pathophysiology and implications for treatment. J Gastrointest Surg 2007;11:286–290.PubMedCrossRefGoogle Scholar
  23. 23.
    Pandolfino JE, El-Serag HB, Zhang Q, Shah N, Ghosh SK, Kahrilas PJ. Obesity: a challenge to esophagogastric junction integrity. Gastroenterology 2006;130:639–649.PubMedCrossRefGoogle Scholar
  24. 24.
    Kahrilas PJ, Dodds W J, Hogan WJ. Effect of peristaltic dysfunction on esophageal volume clearance. Gastroenterology 1988;94:73–80.PubMedGoogle Scholar
  25. 25.
    Diener U, Patti MG, Molena D, Fisichella PM, Way LW. Esophageal dysmotility and gastroesophageal reflux disease. J Gastrointest Surg 2001;5:260–265.PubMedCrossRefGoogle Scholar
  26. 26.
    Fouad YM, Katz PO, Hatlebakk JG, Castell DO. Ineffective esophageal motility: the most common motility abnormality in patients with GERD-associated respiratory symptoms. Am J Gastroenterol 1999;94:1464–1467.PubMedCrossRefGoogle Scholar
  27. 27.
    Herbella FAM, Tedesco P, Nipomnick I, Fisichella PM, Patti MG. Effect of partial and total laparoscopic fundoplication on esophageal body motility. Surg Endosc 2007;21:285–288.PubMedCrossRefGoogle Scholar
  28. 28.
    Kauer WK, Peters JH, DeMeester TR, Ireland AP, Bremner CG, Hagen JA. Mixed reflux of gastric and duodenal juices is more harmful to the esophagus than gastric juice alone. Ann Surg 1995;222:525–533.PubMedGoogle Scholar
  29. 29.
    Tamhankar AP, Peters JH, Portale G, Hsieh CC, Hagen JA, Bremner CG, DeMeester TR. Omeprazole does not reduce gastroesophageal reflux: new insights using multichannel intraluminal impedance technology. J. Gastrointest. Surg. 2004;8:890–897.PubMedCrossRefGoogle Scholar
  30. 30.
    Mainie I, Tutuian R, Shay S, Vela M, Zhang X, Sifrim D, Castell DO. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicenter study using combined ambulatory impedance-pH monitoring. Gut 2006;55:1398–1402.PubMedCrossRefGoogle Scholar
  31. 31.
    Mainie I, Tutuian R, Agrawal A, Adams D, Castell DO. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen fundoplication. Br. J. Surg. 2006;93:1483–1487.PubMedCrossRefGoogle Scholar
  32. 32.
    Pearson JEG, Wilson RSE. Diffuse pulmonary fibrosis and hiatus hernia. Thorax 1971;26:300–305.PubMedCrossRefGoogle Scholar
  33. 33.
    Mays EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobronchial aspiration. A study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial pulmonary fibrosis of obscure etiology. Chest 1976;69:512–515.PubMedCrossRefGoogle Scholar
  34. 34.
    Pellegrini CA, DeMeester TR., Johnson, LF, Skinner DB. Gastroesophageal reflux and pulmonary aspiration: incidence, functional abnormality, and results of surgical therapy. Surgery 1979;86:110–118.PubMedGoogle Scholar
  35. 35.
    Johnson DA, Drane WE, Curran J, Cattau EL Jr, Ciarleglio C, Khan A, Cotelingam J, Benjamin SB. Pulmonary disease in progressive systemic sclerosis. A complication of gastroesophageal reflux and occult aspiration? Arch Intern Med 1989:149:589–593.PubMedCrossRefGoogle Scholar
  36. 36.
    Patti MG, Debas HT, Pellegrini CA. Clinical and functional characterization of high gastroesophageal reflux. Am J Surg 1993;165:163–168.PubMedCrossRefGoogle Scholar
  37. 37.
    Wilshire CL, Salvador R, Sepesi B, Niebisch S, Watson TJ, Litle VR, Peyre CG, Jones CE, Peters JH. Reflux-associated oxygen desaturations: usefulness in diagnosing reflux-related respiratory symptoms. J Gastrointest Surg 2013;17:30–38.PubMedCrossRefGoogle Scholar
  38. 38.
    Metheny NA, Chang YH, Ye JS, Edwards SJ, Defer J, Dahms TE, Stewart BJ, Stone KS, Clouse RE. Pepsin as a marker for pulmonary aspiration. Am J Crit. Care 2002;11:150–154.PubMedGoogle Scholar
  39. 39.
    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;35:303–308.PubMedCrossRefGoogle Scholar
  40. 40.
    Ufberg JW, Bushra JS, Patel D, Wong E, Karras DJ, Kueppers F. A new pepsin assay to detect pulmonary aspiration of gastric contents among newly intubated patients. Am J Emerg Med 2004;22:612–614.PubMedCrossRefGoogle Scholar
  41. 41.
    Farhath S, Aghai ZH, Nakhla T, Saslow J, He Z, Soundar S, Mehta DI. Pepsin, a reliable marker of gastric aspiration, is frequently detected in tracheal aspirates from premature ventilated neonates: relationship with feeding and methylxanthine therapy. J Pediatr Gastroenterol Nutr 2006;43:336–341.PubMedCrossRefGoogle Scholar
  42. 42.
    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 Ped Surg 2006;41:289–293.CrossRefGoogle Scholar
  43. 43.
    D'Ovidio F, Mura M, Tsang M, Waddell TK, Hutcheon MA, Singer LG, Hadjiliadis D, Chaparro C, Gutierrez C, Pierre A, Darling G, Liu M, Keshavjee S. Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg 2005;129:1144–1152.PubMedCrossRefGoogle Scholar
  44. 44.
    El-Seraq HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with esophagitis in United States military veterans. Gastroenterology 1997;113:755–760.CrossRefGoogle Scholar
  45. 45.
    Noth I, Zangan SM, Soares RV, Forsythe A, Demchuk C, Takahashi SM, Patel SB, Strek ME, Krishnan JA, Patti MG, Macmahon H. Prevalence of hiatal hernia by blinded multidetector CT in patients with idiopathic pulmonary fibrosis. Eur. Respir. J. 2012;39:344–351.PubMedCrossRefGoogle Scholar
  46. 46.
    Sweet MP, Herbella FA, Leard L, Hoopes C, Golden J, Hays S, Patti MG. The prevalence of distal and proximal gastroesophageal reflux in patients awaiting lung transplantation. Ann Surg 2006;244:491–497.PubMedGoogle Scholar
  47. 47.
    Salvioli B, Belmonte G, Stanghellini V, Baldi E, Fasano L, Pacilli AM, De Giorgio R, Barbara G, Bini L, Cogliandro R, Fabbri M, Corinaldesi R. Gastro-oesophageal reflux and interstitial lung disease. Dig Liver Dis 2006;38:879–884.PubMedCrossRefGoogle Scholar
  48. 48.
    Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, Sillery JK, Pope CE 2nd, Pellegrini CA. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006;27:136–142.PubMedCrossRefGoogle Scholar
  49. 49.
    Lee JS, Song JW, Wolters PJ, Elicker BM, King TE Jr, Kim DS, Collard HR. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J 2012;39:352–358.PubMedCrossRefGoogle Scholar
  50. 50.
    Bello B, Zoccali M, Gullo R, Allaix ME, Herbella FA, Gasparaitis A, Patti MG. Gastroesophageal reflux disease and antireflux surgery—what is the proper preoperative work-up? J Gastrointest Surg 2013;17:14–20.PubMedCrossRefGoogle Scholar
  51. 51.
    Patti MG, Robinson T, Galvani C, Gorodner MV, Fisichella PM, Way LW. Total fundoplication is superior to partial fundoplication even when esophageal peristalsis is weak. J Am Coll Surg 2004;198:863–870.PubMedCrossRefGoogle Scholar
  52. 52.
    Dallemagne B, Weerts J, Markiewicz S, Dewandre JM, Wahlen C, Monami B, Jehaes C. Clinical results of laparoscopic fundoplication at ten years after surgery. Surg Endosc 2006;20:159–165.PubMedCrossRefGoogle Scholar
  53. 53.
    Heider TR, Behrns KE, Koruda MJ, Shaheen NJ, Lucktong TA, Bradshaw B, Farrell TM. Fundoplication improves disordered esophageal motility. J Gastrointest Surg 2003;7:159–163.PubMedCrossRefGoogle Scholar
  54. 54.
    Bahmeriz F, Dutta S, Allen CJ, Pottruff CG, Anvari M. Does laparoscopic antireflux surgery prevent the occurrence of transient lower esophageal sphincter relaxation? Surg Endosc 2003;17:1050–1054.PubMedCrossRefGoogle Scholar
  55. 55.
    Tedesco P, Lobo E, Fisichella PM, Way LW, Patti MG. Laparoscopic fundoplication in elderly patients with gastroesophageal reflux disease. Arch Surg 2006;141:289–292.PubMedCrossRefGoogle Scholar
  56. 56.
    Ciovica R, Gadenstätter M, Klingler A, Neumayer C, Schwab GP. Laparoscopic antireflux surgery provides excellent results and quality of life in gastroesophageal reflux disease patients with respiratory symptoms. J Gastrointest Surg 2005;9:633–637.PubMedCrossRefGoogle Scholar
  57. 57.
    Hunter JG, Trus TL, Branum GD, Waring JP, Wood WC. A physiologic approach to laparoscopic fundoplication for gastroesophageal reflux disease. Ann Surg 1996;223: 673–687.PubMedCrossRefGoogle Scholar
  58. 58.
    Patti MG, Arcerito M, Tamburini A, Diener U, Feo CV, Safadi B, Fisichella P, Way LW. Effect of laparoscopic fundoplication on gastroesophageal reflux disease-induced respiratory symptoms. J Gastrointest Surg 2000;4:143–149.PubMedCrossRefGoogle Scholar
  59. 59.
    Tutuian R, Mainie I, Agrawal A, Adams D, Castell DO. Nonacid reflux in patients with chronic cough on acid-suppressive therapy. Chest 2006;130:386–391.PubMedCrossRefGoogle Scholar
  60. 60.
    Linden PA, Gilbert RJ, Yeap BY, Boyle K, Deykin A, Jaklitsch MT, Sugarbaker DJ, Bueno R. Laparoscopic fundoplication in patients with end-stage lung disease awaiting transplantation. J Thorac Cardiovasc Surg 2006;131:438–446.PubMedCrossRefGoogle Scholar
  61. 61.
    Hoppo T, Jarido V, Pennathur A, Morrell M, Crespo M, Shigemura N, Bermudez C, Hunter JG, Toyoda Y, Pilewski J, Luketich JD, Jobe BA. Antireflux surgery preserves lung function in patients with gastroesophageal reflux disease and end-stage lung disease before and after lung transplantation. Arch Surg 2011;146:1041–1047.PubMedCrossRefGoogle Scholar
  62. 62.
    Lee JS, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ, King TE Jr, Collard HR. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir. Crit Care Med 2011;184:1390–1394.PubMedCrossRefGoogle Scholar
  63. 63.
    Gasper WJ, Sweet MP, Hoopes C, Leard LE, Kleinhenz ME, Hays SR, Golden JA, Patti MG. Antireflux surgery for patients with end-stage lung disease before and after lung transplantation. Surg Endosc 2008;22:495–500.PubMedCrossRefGoogle Scholar
  64. 64.
    Elicker BM, Golden JA, Ordovas KG, Leard L, Golden TR, Hays SR. Progression of native lung fibrosis in lung transplant recipients with idiopathic pulmonary fibrosis. Respir Med 2010;104:426–433.PubMedCrossRefGoogle Scholar
  65. 65.
    Christie JD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Dobbels F, Kirk R, Rahmel AO, Stehlik J, Hertz MI; International Society of Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart–lung transplant report—2012. J Heart Lung Transplant 2012;31:1073–1086.PubMedCrossRefGoogle Scholar
  66. 66.
    Trulock EP, Christie JD, Edwards LB, Boucek MM, Aurora P, Taylor DO, Dobbels F, Rahmel AO, Keck BM, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult lung and heart–lung transplant report—2007. J Heart Lung Transplant. 2007;26:782–795.PubMedCrossRefGoogle Scholar
  67. 67.
    Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult lung and heart–lung transplant report—2005. J Heart Lung Transplant 2005;24:956–967.PubMedCrossRefGoogle Scholar
  68. 68.
    Blondeau K, Mertens V, Vanaudenaerde BA, Verleden GM, Van Raemdonck DE, Sifrim D, Dupont LJ. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J 2008;31:707–713.PubMedCrossRefGoogle Scholar
  69. 69.
    Fisichella PM, Davis CS, Lundberg PW, Lowery E, Burnham EL, Alex CG, Ramirez L, Pelletiere K, Love RB, Kuo PC, Kovacs EJ. The protective role of laparoscopic antireflux surgery against aspiration of pepsin after lung transplantation. Surgery 2011;150:598–606.PubMedCrossRefGoogle Scholar
  70. 70.
    D'Ovidio F, Mura M, Ridsdale R, Takahashi H, Waddell TK, Hutcheon M, Hadjiliadis D, Singer LG, Pierre A, Chaparro C, Gutierrez C, Miller L, Darling G, Liu M, Post M, Keshavjee S. The effect of reflux and bile acid aspiration on the lung allograft and its surfactant and innate immunity molecules SP-A and SP-D. Am J Transplant 2006;6,1930-1938.PubMedCrossRefGoogle Scholar
  71. 71.
    O'Halloran EK, Reynolds JD, Lau CL, Manson RJ, Davis RD, Palmer SM, Pappas TN, Clary EM, Eubanks WS. Laparoscopic Nissen fundoplication for treating reflux in lung transplant recipients. J Gastrointest Surg 2004;8:132–137.PubMedCrossRefGoogle Scholar
  72. 72.
    Cantu E 3rd, Appel JZ 3rd, Hartwig MG, Woreta H, Green C, Messier R, Palmer SM, Davis RD Jr. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease. Ann Thorac Surg 2004;78:1142–1151.PubMedCrossRefGoogle Scholar
  73. 73.
    Davis RD Jr, Lau CL, Eubanks S, Messier RH, Hadjiliadis D, Steele MP, Palmer SM. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg 2003;125:533–542.PubMedCrossRefGoogle Scholar
  74. 74.
    Fisichella PM, Davis CS, Gagermeier J, Dilling D, Alex CG, Dorfmeister JA, Kovacs EJ, Love RB, Gamelli RL. Laparoscopic antireflux surgery for gastroesophageal reflux disease after lung transplantation. J Surg Res 2011;170:e279–e286).PubMedCrossRefGoogle Scholar
  75. 75.
    Fisichella PM, Davis CS, Lowery E, Ramirez L, Gamelli RL, Kovacs EJ. Aspiration, Localized Pulmonary Inflammation, and Predictors of Early-Onset Bronchiolitis Obliterans Syndrome after Lung Transplantation. J Am Coll Surg 2013;217(1), in press.Google Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2013

Authors and Affiliations

  • Marco E. Allaix
    • 1
  • P. Marco Fisichella
    • 2
  • Imre Noth
    • 3
  • Bernardino M. Mendez
    • 2
  • Marco G. Patti
    • 1
  1. 1.Center for Esophageal Diseases, Department of SurgeryUniversity of Chicago Pritzker School of MedicineChicagoUSA
  2. 2.Swallowing Center, Department of SurgeryLoyola UniversityChicagoUSA
  3. 3.Center for Esophageal Diseases, Department of MedicineUniversity of Chicago Pritzker School of MedicineChicagoUSA

Personalised recommendations